UA126304C2 - Macrocycles as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cycstic fibrosis, and process for making them - Google Patents

Abstract

Compounds of Formula (I), pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed. (I),

Description

The disclosed compounds of formula (1): o and (c) C 1

M i ) t

N

M o pu KU (ha B ; (1) their pharmaceutically acceptable salts, deuterated derivatives of any of the above and metabolites of any of the above. Pharmaceutical compositions containing them, methods of treating cystic fibrosis with their use and methods are also disclosed their production.

This application claims priority to prior US application 62/631,453, filed Feb. 15, 2018, the disclosure of which is incorporated herein by reference in its entirety.

This document discloses a cystic fibrosis transmembrane conductance regulator modulator (CTC), pharmaceutical compositions containing the modulator, methods of treating cystic fibrosis, and a method of manufacturing the modulator.

Cystic fibrosis (CF) is a recessive genetic disease that affects about 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no complete cure.

In CF patients, mutations in CETK, endogenously expressed in the respiratory epithelium, lead to a decrease in apical anion secretion, causing an imbalance in ion and fluid transport. The resulting reduction in anion transport contributes to the accumulation of mucus in the lungs and the associated microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients commonly suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, can lead to death. In addition, most men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

Sequence analysis of the CETK gene has revealed a variety of disease-causing mutations (Sitsipu, SA et al. (1990) Maishte 346:366-369; Oeap, M. et al. (1990) SeiI 61:863:870; and

Keget, B-5. her a. (1989) Zsivepse 245:1073-1080; Keget, В-5 ейі ай. (1990) Rhos. Mai! Asad from

IBA 87:8447-8451). To date, more than 2,000 mutations in the CF gene have been identified; currently, the CETC2 database contains information for only 322 of these identified mutations, with sufficient evidence to identify 281 mutations as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CETC amino acid sequence, and is commonly referred to as the E5O8ae mutation. This mutation occurs in approximately 70 to 95 cases of cystic fibrosis and is associated with severe disease.

Deletion of residue 508 in CETC prevents proper folding of the nascent protein. This results in the inability of the mutant protein to leave the endoplasmic reticulum (EC) and move to the plasma membrane. As a result, the number of SETK channels for the transport of anions present in the membrane is significantly less than that observed in cells that

Zo express wild-type CETCs, that is, CETCs that do not have mutations. In addition to impaired migration, the mutation leads to defects in the gating mechanism of ion channels. Together, the reduced number of channels in the membrane and the defective gating mechanism of ion channels lead to reduced anion and fluid transport across the epithelium. (Scipiop, R. M. (1990), EAZEV U. 4: 2709-2727). Defective channels due to E508aeee mutations! are still functional, although less functional than wild-type CETK channels. (Oaietapv ei ai. (1991), Mayte Gopa. 354: 526-528; Razuk apa

EozKei (1995), U. SeiI. Viospet. 270: 12347-50). In addition to E5ovavea, other disease-causing mutations in CETCs that result in defective migration, synthesis, and/or gating of ion channels may be upregulated or downregulated to alter anion secretion and alter disease progression and/or severity.

CETK is a cAMP/ATP-mediated anion channel that is expressed in various cell types, including cells of the absorptive and secretory epithelium, where it regulates the flow of anions through the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, the normal functioning of CETC is crucial for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CETC consists of approximately 1,480 amino acids that encode a protein that consists of a tandem repeat of transmembrane domains, each of which contains six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are connected by a large, polar, regulatory (K) domain with many phosphorylation sites that regulate channel activity and cell migration.

Chloride transport is carried out due to the coordinated activity of EMasS and CETE, present on the apical membrane, and the Ma--K--ATPase pump and SiI channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the inside leads to accumulation of intracellular chloride, which can then passively leave the cell through SI channels, resulting in vectorial transport. Location

The Ma-/ 2CI-/ K- cotransporter, the Ma--K--ATPase pump and K» channels of the basolateral surface on the basolateral surface and SETK on the inner side coordinate chloride secretion through SETK on the inner side. Because water is probably never actively transported by itself, its flow across the epithelium depends on minute transepithelial osmotic gradients generated by the bulk flux of sodium and chloride.

Accordingly, there is a need for new methods of treatment of mediated diseases

SET.

This document discloses new compounds, including compounds of formulas (I), (IPI-A), (II-B), (PI-A), (Ш-B), (IM-A), (IM-B), (1M-O), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-O), their pharmaceutically acceptable salts and deuterated derivatives of any - any of the above. For example, compounds of Formula (1) can be described as:

But oh well

Kk c (k7) and c (its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - Ring A is a phenyl, 5-membered heteroaryl ring or b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring ХО is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X is 0, MH or M (C1-C4 alkyl); - each K1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo group, hydroxyl th group, cyano group and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached, form a 5-- b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl

From groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1, 2, C or 4; and - 7 is a bivalent linker of the formula (MG, where: - r is 1, 2, 3, 4, 5 or 6;

- each Y is independently selected from С(К8)(КУ) groups, -0-- and -МАр-- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each К8 and КУ is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KB is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, ring Y in Formula (I) is pyridin-2(1H)-one, pyrrolidin-2-one, or imidazolidinyl-2-one.

Also disclosed in this document are pharmaceutical compositions containing at least one of the new compounds described in this document, or at least one pharmaceutically acceptable salt thereof, and these compositions may additionally include at least one additional active pharmaceutical ingredient and/or at least one carrier. Also disclosed are methods of treating cystic fibrosis mediated by CETC, comprising administering at least one of the novel compounds described herein, or at least one pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition containing at least one additional component, to a sub object that needs it.

Also disclosed are methods of treating CETE-mediated cystic fibrosis comprising administering at least one of the novel compounds described herein, or at least one pharmaceutically acceptable salt, (K)-1-(2,2-difluorobenzo|94|/1,3| dioxol-5-yl)-M-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl cyclopropanecarboxamide (compound 1) of M-(2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl|-1,4-dihydro-4-oxoquinoline-3-carboxamide (compound II), optionally as part of at least one pharmaceutical composition containing at least one additional component, in a patient who needs it.

Brief description of graphic materials

Fig. 1 shows the structures of non-limiting examples of novel compounds disclosed herein.

Fig. 2 is a representative list of CETE mutations.

Definition

As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon (containing, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms). Alkyls can be substituted or unsubstituted, branched or unbranched.

As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms.

As used herein, the term "cycloalkyl group" refers to a cyclic non-aromatic hydrocarbon containing from 3 to 12 carbon atoms in the ring (eg, from 3 to 10 carbon atoms). Cycloalkyl groups include monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spirocyclic rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro|2.2|Ipentane and dispiro(2.0.2.1)heptane.

Cycloalkyl groups can be substituted or unsubstituted.

As used herein, the term "alkyl group" refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. Alkoxy groups can be substituted or unsubstituted, branched or unbranched.

As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms.

As used herein, the term "heteroaryl ring" refers to an aromatic ring containing at least one ring atom that is a heteroatom, such as

Oh, Mabo 5.

As used herein, the term "heterocyclic ring" refers to a non-aromatic hydrocarbon containing from C to 12 ring atoms (eg, from C to 10 atoms) containing at least one ring atom that is a heteroatom, such as O, M, or 5. "Heterocyclic" rings include monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused and spiro rings, including monospiro and dispiro rings.

Examples of nitrogen protecting groups include, for example, tert-butylcarbamate (Boc), benzyl (Bp), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Etos), benzylcarbamate (Cp27), methylcarbamate, ethylcarbamate, 2 ...

toluenesulfonamide. A complete list of nitrogen protective groups can be found in UUtsi5, R. 5. M. "Sgeepe 5

Rgoyesiime SgotsMyrz ip Ogdapis Zupipebviv: ГЯЯ Eаиоп," 2014, dopp U/ieu apa 5opv5. "Substituted", preceded by the term "optionally" or not, indicates that at least one hydrogen in the "substituted" group is replaced by a substituent. If unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each position of the substituted group, and when more than one position in any given structure may be substituted by more than one substituent selected from the specified group, the substituent may be the same or different in each position.

As used herein, the term "deuterated derivative" refers to the same chemical structure but with one or more hydrogen atoms replaced by a deuterium atom.

As used herein, the term "CETC" means cystic fibrosis transmembrane conductance regulator.

As used herein, the term "mutations" may refer to mutations in a gene

SETK or SETEK protein. "SETEK gene mutation" refers to a mutation in the SETE gene, and "protein mutation

CETE" refers to a mutation in the CETE protein. A genetic defect or mutation or a change in nucleotides in a gene generally leads to a mutation in the CETE protein, which is translated from this gene, or to a frameshift.

The term "E5Ovaeii" refers to a mutant CETE protein that lacks the amino acid phenylalanine at position 508.

In this context, a patient who is "homozygous" for a particular gene mutation has the same mutation for each allele.

In this context, a patient who is "heterozygous" for a particular gene mutation has that mutation on one allele and another mutation on the other allele.

As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound or molecule, such as a protein. For example, a SETK modulator is a compound that increases the activity of SETK. Increased activity as a result of a SET modulator includes, but is not limited to, compounds that correct, potentiate, stabilize, and/or enhance SET.

As used herein, the term "SETC corrector" refers to a compound which

Zo facilitates the processing and transport of CETE to increase the amount of CETE on the cell surface. Compounds of formulas (1), (PI-A), (1-8), (PI-A), (PI-B), (IM-A), (IM-B), (IM-C), (M -A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-O)), compound II, compound IM and their pharmaceutically acceptable salts disclosed herein , are correctors of SETEK.

As used herein, the term "SETK enhancer" refers to a compound that increases the activity of the cell-surfaced SETK protein channel, resulting in enhanced ion transport. Compound II disclosed herein is a SETEK enhancer.

As used herein, the term "active pharmaceutical ingredient" ("API") refers to a biologically active compound.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of the present disclosure wherein the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of this disclosure include salts derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Bergu et al. describe in detail the pharmaceutically acceptable salts in y). Rpagtaseshiisa! Zsiepse5, 1977, 66, 1-19.

As used herein, the term "amorphous" refers to a solid material that has no long-range order in the arrangement of molecules. Amorphous solids are typically supercooled liquids in which the molecules are randomly arranged, so there is no well-defined arrangement, such as molecular packing, and no long-range order. Amorphous solids are usually isotropic, that is, they exhibit the same properties in all directions and do not have defined melting points. For example, an amorphous material is a solid material that does not have characteristic sharp crystalline peaks on an X-ray powder diffraction (XRD) pattern (ie, is not crystalline as defined by XRD). Instead, one or more broad peaks (such as halos) appear on his HERO chart. Broad peaks are characteristic of an amorphous solid.

IDiv. 05 2004/0006237 for comparison of ХКРО of amorphous material and crystalline material).

As used herein, the term "essentially amorphous" refers to a solid material having little or no long-range order in the position of the molecules. For example, substantially amorphous materials have a crystallinity of less than 15 95 (eg, a crystallinity of less than 10 95 or a crystallinity of less than 5 95). It should also be noted

that the term "essentially amorphous" includes the descriptor "amorphous" which refers to materials that do not have (0 95) crystallinity.

As used herein, the term "dispersion" refers to a dispersed system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or carrier). The size of the dispersed phase can vary significantly (for example, colloidal particles ranging in size from a nanometer to several microns). As a rule, dispersed phases can be solids, liquids or gases. In the case of a solid dispersion, both the dispersed and continuous phases are solid. When used for pharmaceutical purposes, a solid dispersion may include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or, alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments of the invention, the solid dispersion includes a polymer that is a dispersed phase, and a drug that is a continuous phase. Alternatively, the solid dispersion includes the drug constituting the dispersed phase and the polymer constituting the continuous phase.

The terms "patient" and "subject" are used interchangeably and refer to an animal, particularly a human.

The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (eg, attenuating CF or a CF symptom or reducing the severity of CF or a CF symptom). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, for example, Gisua (1999) Te Agi, zsiepse apa TesppoYodu oi Rpaptaseshisa! Spolukaipo).

As used herein, the terms "treating," "treating," and the like generally refer to ameliorating CF or its symptoms or reducing the severity of CF or its symptoms in a subject. "Treatment" in the context of this specification includes, but is not limited to: increasing the subject's growth, increasing weight, decreasing mucus in the lungs, improving pancreatic and/or liver function, decreasing chest infections, and/or decreasing cough or shortness of breath . Improvement or reduction in the severity of any of these symptoms can be readily assessed by standard methods and techniques known in the art.

As used herein, the term "in combination 3" when used in relation to two or more compounds, agents or additional active pharmaceutical ingredients means the administration to a patient of two or more compounds, agents or active pharmaceutical ingredients before, simultaneously with or after each other.

The terms "about" and "about," when used in connection with doses, amounts, or percentages by weight of the ingredients of a composition or dosage form, include the value of the stated dose, amount, or percentage by weight, or a range of the dose, amount, or percentage by weight that, as recognized by a person skilled in the art, provide a pharmacological effect equivalent to that obtained from the specified dose, amount or mass percentage.

One of ordinary skill in the art will understand that when an amount of a "compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. It should be noted that the amounts of compounds or pharmaceutically acceptable salts thereof disclosed herein are based on their free base form. For example, "10 mg of at least one compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof" includes 10 mg of a compound of formula (I) and a concentration of a pharmaceutically acceptable salt of compounds of formula (I) equivalent to 10 mg of a compound of formula (1).

Suitable pharmaceutically acceptable salts are, for example, the salts disclosed in 5M Wegde, ei a). U. Rnaptasetsiis! Zsiepsev, 1977, 66, 1-19. For example, in Table 1 of this article, the following pharmaceutically acceptable salts are presented:

Table 1

Hydrabamino HER

Non-limiting examples of pharmaceutically acceptable salts derived from the corresponding acids include: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; as well as salts formed using other methods used in the art, such as ion exchange.

Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, polonate heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, Z- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium and M(C1-4 alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

The exact amount of the pharmaceutical composition required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the disease,

From a specific agent, the method of its introduction, etc. The compositions according to this invention can be formulated in the form of a single dosage form for ease of administration and uniformity of dosage.

The term "standard dosage form" as used herein refers to a physically discrete unit of agent suitable for a patient to be treated. However, it should be understood that the general daily use of the compounds and compositions of this disclosure will be decided by the treating physician within the framework of sound medical judgment. The particular effective dose level for any particular patient or organism will depend on many factors, including the disorder being treated and the severity of the disease; the activity of the specific API used; the specific composition used; age, body weight, general health, gender and diet of the patient; the time of administration, the method of administration and the rate of excretion of the specific compound used; duration of treatment; drugs used in combination or coinciding with the particular compound used, and similar factors well known in medicine. The term "patient" as used herein refers to an animal, such as a mammal, and even more so, such as a human.

In some embodiments, the disclosure is also directed to methods of treatment using isotopically labeled compounds of the above compounds having the same structures as those disclosed herein, except that one or more atoms therein have been replaced by an atom or atoms that have an atomic mass or mass number that is different from the atomic mass or mass number of an atom normally found in nature (isotope label). Examples of isotopes that are commercially available and suitable for this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2H, 3H, 13C, 14C, 15M, 180, 170, 3P, 32P , 355, 18BE and Z6SI, respectively.

Isotopically labeled compounds and salts can be used in many useful ways. They may be suitable for drugs and/or different types of assays, such as assays of substrate distribution in tissues. For example, compounds labeled with tritium (CH) and/or carbon-14 (140) are particularly useful for various types of assays, such as tissue substrate distribution assays, due to their relatively simple preparation and excellent detectability. For example, deuterium (2H)-labeled compounds are therapeutically useful with potential therapeutic advantages over non-2H-labeled compounds. In general, compounds and salts labeled with deuterium (2H) may have higher metabolic stability compared to unlabeled isotopes due to the kinetic isotope effect described below. Higher metabolic stability is directly expressed in an increase in the half-life of ip mimo or in lower doses, which may be desirable. Isotopically labeled compounds and salts can usually be obtained by following the techniques disclosed in the synthesis schemes and corresponding description, in the example section and in the preparation section of this text, replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

In some embodiments, the isotope-labeled compounds and salts are labeled with deuterium (2H). In some specific embodiments, the isotopically labeled compounds and salts are labeled with deuterium (2H), where one or more hydrogen atoms are replaced by deuterium. In chemical structures, deuterium is represented as "2H" or "p".

Compounds and salts labeled with deuterium (2H) can affect the oxidative metabolism of the compound by means of the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction that occurs as a result of the exchange of isotopic nuclei, which, in turn, is caused by a change in the ground state energy required for the formation of a covalent bond after this isotopic exchange. The exchange of a heavier isotope usually results in a decrease in the energy of the ground state of the chemical bond and thus causes a decrease in the rate-limiting bond gap. If the bond break occurs in or near the region of the saddle point along the multiproduct reaction coordinate, the distribution ratios of the products can be significantly altered. To clarify, if deuterium is bound to a carbon atom in a non-replaceable position, differences in speed are typical

КМ/ЖО - 2-7. For further discussion, see 5 Nagresop and KO Tipo, Oeshegisht and Ogyd

Oivsomegu apa Yuemeiortepi, App. Sept. Honey. Spent 2011, 46, 403-417; apa T.b. bSapi "O5ipd deshegisht ip agid aizsomegu: Ivamipud (pe Iabei ip Shte agid'.. Mea. Spet. 2014, 57, 3595-3611, relevant parts of which are independently incorporated into this document by reference.

The concentration of isotopes (eg, deuterium) included in the isotope-labeled compounds and salts of this description can be determined using the isotopic enrichment factor. The term "isotopic enrichment factor" as used in this document refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. In some embodiments, if the substituent in the compound of the disclosure is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5 95 deuterium incorporation into each designated deuterium atom), at least 4000 (deuterium incorporation of 60 95), not less than 4500 (inclusion of deuterium 67.5 95), not less than 5000 (inclusion of deuterium 7595), not less than 5500 (inclusion of deuterium 82.5 95), not less than 6000 (inclusion of 60 deuterium 90 95), not less than 6333 .3 (inclusion of deuterium 95 95), not less than 6466.7 (inclusion of deuterium 97 95), not less than 6600 (inclusion of deuterium 99 95) or not less than 6633.3 (inclusion of deuterium 99.5 b).

In the discovery and development of therapeutic agents, a specialist in this field tries to optimize pharmacokinetic parameters while preserving the desired properties of the drug.

It is reasonable to assume that many compounds with poor pharmacokinetic profiles undergo oxidative metabolism.

One of ordinary skill in the art will appreciate that deuteration of one or more metabolically labile positions in a compound or active metabolite can lead to an improvement in one or more of the superior properties of the OMRC while maintaining biological activity compared to the corresponding hydrogen analogs. A remarkable property or properties

OMRCs can affect the action, half-life, clearance, metabolism, and/or even food requirements for optimal drug absorption. Deuteration may also alter metabolism at other non-deuterated positions of the deuterated compound.

In some embodiments, the disclosure includes deuterated derivatives of the novel compounds disclosed herein and pharmaceutically acceptable salts thereof. Non-limiting examples of deuterated compounds are disclosed in FIG. 1.

Each compound described herein, in particular, compounds of formulas (1), (P-A), (1-8), (PI-A), (PI-B), (IM-A), (IM-B), (IM-C), (M-A), (M-B), (MI-A), (MI-B), (MI-S) and (MI-Y), compounds of ІІ, ІІ and IM, their pharmaceutically acceptable salts and deuterated derivatives of any of the above can be independently administered once daily, twice daily, or three times daily. In some embodiments, at least one compound selected from compounds of formulas (I), (P-A), (1-8), (PI-A), (PI-B), (IM-A), (IM-B ), (IM-C), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-Y), their pharmaceutically acceptable salts and deuterated derivatives of any of the above, administered once a day.

In some embodiments, at least one compound selected from compounds of formulas (I), (PI-A), (P-8B), (SHI-A), (P-B), (IM-A), (IM-B ), (IM-C), (M-A), (M-B), (MI-A), (MI-B), (MI-CE) and (MI-B), their pharmaceutically acceptable salts, and deuterated derivatives of any of the above, is administered twice a day. In some embodiments, at least one compound selected from compound I and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, at least one compound selected from compound I and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound selected from compound PI and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, at least one compound selected from compound IM and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound selected from compound IM and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, a deuterated derivative of compound II, PS, and/or IM, or a pharmaceutically acceptable salt thereof, is used in any of these embodiments.

In some embodiments, from 10 mg to 1500 mg of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound or salt is administered intravenously.

As stated above, this document discloses the compounds of formula (1): o Kf v2 Z 1 (ka m V") t

N

Кк с (Рг) в (), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where:

- Ring A is a phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring ХО is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X represents 0, MH or M (C1-C4 alkyl); - each C1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-- b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is 0, 1 , 2, 3, 4, 5 or 6; - each U is independently selected from C(K5)(Kb) groups, -0-- and -MVa- groups, where the heteroatom in -(U)K-

K?7 is not connected to another heteroatom in -(M)K-K7, where: - each H5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or 5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and

Zo - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1, 2, C or 4; and - 7 is a bivalent linker of the formula (MG, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(К8)(К9) groups, -0-- and -МАр -- groups where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula (1I-A) or (PI-B):

N

M v3 C of them 2 (g) in (IPI-A) or o K / v2 Z 1 (vl) 7 in t

N

M-x 7 sh:AOSH (te) and vo (P-V), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - Ring A is a phenyl, 5-membered heteroaryl ring, or b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring JO is a phenyl ring, a 5-membered heterocyclyl ring, b-ch- one-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - each K1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, a cyano group and a hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens , a cyano group and a hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halo ene, hydroxyl group, oxo group, cyano group and - (YUK-K?7 groups, or optionally two KA together with the atoms to which they are attached, form a 5-- b-membered cycloalkyl or heterocyclyl ring, which is not necessarily necessarily and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom

Zo together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1, 2, C or 4; - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each I is independently selected from C(K8) (K9) groups, -0-- and -MAB- - groups where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, C1-C2 haloalkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-02 haloalkyl groups, and - each KB is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula (PI-A) or (III-B):

о оо (В2)в У 1

Ho m v ) t

N

4

M in Si" 7 in Z (vd in (I-A) or o o o (nu U 1 su chai in ) t

N

M M---7

In Z

(code Kk (PI-B), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - Ring A is phenyl, 5-h -one heteroaryl ring or b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring Y is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - each K1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0.1 , 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo groups , a hydroxyl group, a cyano group and - (YUK-K7 groups or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups, selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not connected to another heteroatom in -(U)K-H7, where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4

From alkyl groups and C3-5 cycloalkyl groups, or 5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and

- K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2; - 7 is a bivalent linker of formula (I) g, where: - g is equal to 3, 4 or 5; - each Y is independently selected from C(К8)(К9) groups, -0-- and -МАр-- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula IM-A:

Moss t vd

I -ya«eh - M -EZH

М M в ж m 4 3 its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - Ring ХО is a phenyl ring, 5-h- one-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - X is 0, MH or M (C1-C4 alkyl); - each K1 is independently selected from C1- C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1 - C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl;

Zo - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2 , 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2;

- 7 is a bivalent linker of formula (I) g, where: - g is equal to 3, 4 or 5; - each Y is independently selected from C(К8)(К9) groups, -0-- and -МАр-- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula IM-B:

M M vZ p

УА их т З Вр б (code Кк (сб), в (М.В), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry ; - Ring ХО is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each K1 is independently selected from C1-C2 alkyl groups . groups, C1-C2 alkoxy groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached , form a 5-b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups groups where:

Ko) - K equals 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2; - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KB is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula IM-C: o o o o (c) M

I-th

M. - Mich

H. M. M

Zhk--/ With M

Kk (Ka - eh A

From the age of 8

Ck (svv) in (M-Cb) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - each K1 is independently selected from C1-C2 alkyl groups, C1-C2 alkoxy groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkoxy groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached, form a 5-b-membered cycloalkyl or heterocyclyl ring, which optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups group, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not connected to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or 5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and

Zo - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2; - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula MU-A:

oh oh (woo What

M

4 Shk " 3 same in 4 With its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - carbon, marked ", has 5-stereochemistry or K-stereochemistry; - Ring ХО is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each C1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(K5)(Kb) groups, -0-- and -MVa- groups, where the heteroatom in -(U)K-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - PH7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2; - 7 is a bivalent linker of the formula (g, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0-- and -МАр-- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each 8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each KO independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula M-B:

o o o (B2)e M

I'M FROM '

Zh M tr )t

AI what; - honey

M

M och (ka vi (svev"), (M-B), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - Ring ХО represents a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each K1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1- C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo groups , hydroxyl group, cyano group and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached, form a 5-b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups , where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2; - r equals 3, 4 or 5; and - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula MI-A or

MI-V:

ОО оо (c) M j 7 s 1 --(8

M XX

M v3 si» 2 v Z (KO d y: (MI-A) or o oo (vu U a sa s 1 --8 4 HO

M

C is a pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - Ring ХО is a phenyl ring, a 5-membered heterocyclyl ring , b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - each K1 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1- C2 of halogenoalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached, form a 5-b-membered cycloa an alkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K equals 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is not necessarily independently substituted by one or more groups,

With selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl group,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens;

- a is equal to 1 or 2; - 7 is a bivalent linker of formula (I) g, where: - g is equal to 3, 4 or 5; - each Y is independently selected from C(К8)(К9) groups, -0-- and -МАр- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen , halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Kb is independently selected from hydrogen and C1-C2 alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula MI-C or 10. MI-0:

M

VZ si, / (c) v3 vdo

Ch (se, (MI-S) or o oo (2 U och 7 s 1 (tu 4 4

M

ANYA

(ka vi (sulphur, (MI-5), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein: - the carbon designated "has 5-stereochemistry or K-stereochemistry; - the YO ring is a phenyl ring , 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - X is O, MH or M (C1-C4 alkyl); - each K1 independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (YUK-K7 groups, or optionally two K4 together with an atom amines to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6;

- each U is independently selected from С(К5)(Кб) groups, -0-- and -МВа- groups, where the heteroatom in -(У)К-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - a is equal to 1 or 2; - r is equal to C or 4; and - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups.

Also disclosed herein are compounds having a formula selected from any of the formulas depicted in FIG. 1 and their pharmaceutically acceptable salts.

In some embodiments, at least one compound selected from the novel compounds described herein, their pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound selected from Compound II, its pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, at least one compound selected from the novel compounds described herein, their pharmaceutically acceptable salts, and deuterated derivatives of the above is administered in combination with at least one compound selected from compound X and its pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the novel compounds disclosed herein, their pharmaceutically acceptable salts, and deuterated derivatives thereof is administered in combination with at least one compound selected from compound IM and its pharmaceutically acceptable salts. In some embodiments, at least

One compound selected from the novel compounds described herein, their pharmaceutically acceptable salts and deuterated derivatives of the above is administered in combination with Compounds

It or a pharmaceutically acceptable salt or deuterated derivative thereof and with at least one compound selected from compound PI, its pharmaceutically acceptable salts and deuterated derivatives of any of the above. In some embodiments, at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts, and deuterated derivatives of any of the above compounds is administered in combination with at least one compound selected from compound I, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the above and at least one compound selected from compound IM, its pharmaceutically acceptable salts and deuterated derivatives of any of the above.

In some embodiments, at least one new compound (and/"or at least one pharmaceutically acceptable salt thereof and/"or at least one deuterated derivative of such compound or salt) can be administered in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from: (a) Compound II:

M

(o) in U on

E Ge) about E M

ON

(3)

OH (and its pharmaceutically acceptable salts.

The chemical name of Compound II is (K)-1-(2,2-difluorobenzoi|94|I,Z|dioxol-5-yl)-M-(1-(2,3-dihydroxypropyl)-6-fluoro-2 -(1-hydroxy-2-methylpropan-2-yl)-1H-indol-B-yl)ucyclopropanecarboxamide;

PI compounds:

he (c) (c) su

N

M and its pharmaceutically acceptable salts.

The chemical name of the compound PShSh is M-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxami d; and

IM compounds: (c) on

Mo 54 | ХХ

E o (c) p and its pharmaceutically acceptable salts.

The chemical name of the compound M is 3-(6-(1-(2,2-difluorobenzoyl)(/1,3)dioxol-5-ylcyclopropane-1-carboxamide)-3-methylpyridin-2-yl)benzoic acid. in some embodiments, the compound of formula (I) and/or its pharmaceutically acceptable salt can be administered in combination with compound II and/or its pharmaceutically acceptable salt. In some embodiments, the compound of Formula (I) and/or its pharmaceutically acceptable salt can be administered in in combination with Compound I and/or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof may be administered in combination with Compound I and/or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula ( I) and/or its pharmaceutically acceptable salt can be administered in combination with Compound II and/or its pharmaceutically acceptable salt and Compound I and/or its pharmaceutically acceptable salt. In some embodiments, the compound of Formula (I) and/or its pharmaceutically acceptable salt can be added in combination with Compound | and/or its pharmaceutically acceptable salt and Compound IM and/or its pharmaceutically acceptable salt.

In one aspect, the disclosure provides a pharmaceutical composition containing a compound of formula (I) and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In one aspect, the disclosure provides a pharmaceutical composition containing a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a compound II and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure provides a pharmaceutical composition containing a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a compound IH and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure provides a pharmaceutical composition containing a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a compound II and/or a pharmaceutically acceptable salt thereof

Z is an acceptable salt, compound Ш and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Any of the novel compounds described herein, such as, for example, the compounds of formula (I) and their pharmaceutically acceptable salts, as well as deuterated derivatives of such compounds and salts, may be included in a single pharmaceutical composition or individual pharmaceutical compositions in combinations with other additional active pharmaceutical ingredients (for example, compound HER, I or IM or a pharmaceutically acceptable salt or deuterated derivative of such compound or salt). Such pharmaceutical compositions can be administered once a day or several times a day, for example, twice a day. In some embodiments, the disclosure relates to a pharmaceutical composition comprising at least one compound selected from any of the compounds disclosed herein and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present invention, a pharmaceutical composition is disclosed, containing at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from compound HER and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable salt thereof. acceptable medium.

In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from compound I and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier .

In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound selected from the novel compounds described herein and pharmaceutically acceptable salts thereof, at least one compound selected from Compound I and its pharmaceutically acceptable salts, at least one compound selected from Compounds I and its pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from Compound AI and pharmaceutically acceptable salts thereof, at least one compound selected from compound IM and its pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions disclosed herein contain at least one additional active pharmaceutical ingredient. In some embodiments, at least one additional active pharmaceutical ingredient is a CETK modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a NET corrector. In some embodiments, at least one additional active pharmaceutical ingredient is an enhancer

NETWORK In some embodiments, the pharmaceutical composition contains (i) compounds of formulas (I), (P-A), (P-B), (PI-A), (PI-B), (IM-A), (IM-B ), (IM-C), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-U) or their pharmaceutically acceptable salts or deuterated a derivative of such a compound or salt; and (iii) at least two additional active pharmaceutical ingredients, one of which is a SETEK corrector and one of which is a SETEK enhancer.

In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infectives

From means and anti-inflammatory means.

The pharmaceutical composition may additionally contain at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable carriers and pharmaceutically acceptable adjuvants. In some embodiments, at least one pharmaceutically acceptable product is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

It will also be understood that a pharmaceutical composition of the present disclosure, including a pharmaceutical composition that contains the combinations previously described, can be used in combination therapy; that is, the compositions can be administered simultaneously with, before or after at least one additional active pharmaceutical ingredient or medical procedures.

Pharmaceutical compositions containing these combinations are suitable for the treatment of cystic fibrosis.

As described above, the pharmaceutical compositions described herein may optionally additionally contain at least one pharmaceutically acceptable carrier.

At least one pharmaceutically acceptable carrier may be selected from adjuvants and carriers.

At least one pharmaceutically acceptable carrier used in this disclosure includes any and all solvents, diluents, other liquid carriers, dispersing agents, suspending agents, surfactants, isotonic agents, thickeners, emulsifying agents, preservatives, solids binders and lubricants depending on the specific desired dosage form. Keptipdiop: Te 5siepse apa Rgasiise oi Ripagtasu, 2151 eaiiop, 2005, ey. O.V. Tgtou, Pirripsoii UMiShat5 in UMiKip5, RNiadeirnia, apa Epsusioredia oii

Ripaptaseshiisa! Thesppoiodu, ev. in). Zmagbgisk apa u. b. Wow, 1988-1999, Mags! OekkKeg, Mem

UogKk discloses the various carriers used in the formulation of pharmaceutical compositions and the known methods of their preparation. Except that any standard carrier may be incompatible with the substance or its derivatives, for example by causing any undesirable biological effect or otherwise adversely interacting with any other component(s) of the pharmaceutical composition, its use is also considered within the scope of this invention.

Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffering agents (eg, phosphates, glycine, bo sorbic acid, and potassium sorbate) , mixtures of incomplete glycerides of saturated vegetable fatty acids, water, salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth , malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), butters or oils (such as peanut butter, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide) , pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants .

In some embodiments, the methods of the disclosure employ administering to a patient in need thereof at least one compound selected from any of the compounds of formula I and pharmaceutically acceptable salts thereof, and at least one compound selected from compound I, compound

And, IM compounds and pharmaceutically acceptable salts of any of the above.

Any suitable pharmaceutical compositions known in the art can be used for the novel compounds described herein, compound II, compound II, compound IM, and their pharmaceutically acceptable salts. Some examples of pharmaceutical compositions of compound I! and pharmaceutically acceptable salts thereof can be found in WO 2011/119984 and WO 2014/015841, all of which are incorporated herein by reference in their entirety. Some examples of pharmaceutical compositions of compound I and its pharmaceutically acceptable salts can be found in

MO 2007/134279, MO 2010/019239, MO 2011/019413, UMO 2012/027731 and UMO 2013/130669, all of which are incorporated herein in their entirety by reference. Examples of compositions containing compound PI-a and pharmaceutically acceptable salts thereof can be found, for example, in UMO 2014/078842 and UMO 2018/227049, which are incorporated herein by reference. Some examples of pharmaceutical compositions of compound IM and its pharmaceutically acceptable salts are possible

See UMO 2010/037066, UMO 2011/127241, MOU 2013/112804 and UMO 2014/071122, all of which are incorporated herein in their entirety by reference.

In some embodiments, a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof is administered with a pharmaceutical composition comprising compound PP and compound I.

Pharmaceutical compositions containing compound II and compound PI are disclosed in PCT publication Mo M/O 2015/160787, incorporated herein by reference. An illustrative example embodiment is illustrated in Table 2 below:

Table 2

Exemplary tablets containing 100 mg of compound II and 150 mg of compound IP. 11111111 DIngredient 77777771 | Quantity per tablet (ml)

Compound II 5OO (dispersion obtained

Intragranular by spray drying) 125 (80 95 wt. compound Ii, 20 95 wt.

NRMS

Compound SH 500 (80 95 wt. compound IP, 19.5 95 wt. 187.5

NRMSAB-NI; 0.5 95 wt. And sodium lauryl sulfate) 11111111 | Microcrystalline cellulose.//-:/ | 1914 11111111 |Kroskarmelozanatryu.d/-:/ / | 296 11111100 FDUsyogo////7777777711111111 11111111 47351 11111111 | 11111110 FDUsogo/////77777777777771111|Y1117111711841 (Total, uncoated tablets| /////////ggggssssssss11111111111111Й1111111115918С1С (Total coated tablets.y/ | (77777717 Й71717171717161717171617171716171

In some embodiments, a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutical salts thereof is administered with a pharmaceutical composition comprising Compound I. Pharmaceutical compositions comprising Compound I are disclosed in PCT Publication Mo UMO 2010/019239, incorporated into this document by reference. An illustrative example of an embodiment is illustrated in the Table

From here on:

Table C

Ingredients for example tablets of compound PI.

Composition of the tablet Percentage content of the dose Dose of Mo batch uy wt./wt. (mg) (in

Compound PI 500 (80 90 wt. compound PIP, 19.5 95 wt. o

NRMSA5-NS; 0.5 95 wt. 34.09 95 187.5 23.86 sodium lauryl sulfate) 30.51 bo 167.8 21.36 30.40 bo 167.2 21.28

Croscarmellose sodium 3.000 90 16.50 2.100 0.500 9 2.150 0.3500

Colloidal silicon dioxide 0.500 95 2.750 0.3500 1.000 9e 5.500 0.7000 100 Fe

Additional pharmaceutical compositions containing compound II are disclosed in PCT Mo UMO publication 2013/130669, incorporated herein by reference. Typical mini-tablets (2 mm diameter, 2 mm thickness, each mini-tablet weighs about 6.9 mg) were formulated to contain approximately 50 mg of compound HER per 26 mini-tablets and approximately 75 mg of the PI compound into 39 mini-pills using the amounts of ingredients listed in Table 4 below.

Table 4

Ingredients for mini tablets of 50 and 75 mg

Percentage content Dose (mg) Dose (mg) Mo sh . y o y ke o party

The composition of the tablet, the dose, the content of the active substance, the content of the active substance, o () uyu wt./wt. substance 50 mg/| substance 75 mg

PI 500 compound (80 95 wt. PP compound, 19.5 95 wt. NRMSAV-NO; 0.5 95 wt. 35 62.5 33.8 17534 of sodium lauryl sulfate) 675.2 109.8 2050.2 100.06

Croscarmellose sodium 71117601 7107. | 161 | zol

Colloidal silicon dioxide 74.19 178.6 5003.15

In some embodiments of the invention, pharmaceutical compositions are tablets. In some embodiments of the invention, tablets are suitable for oral administration.

The compound, their pharmaceutically acceptable salts and deuterated analogues of any of the above and the pharmaceutical compositions of this disclosure either as monotherapy or in combination therapy are suitable for the treatment of cystic fibrosis.

In some embodiments, methods of treating, alleviating, or symptomatically treating cystic fibrosis in a patient are disclosed herein, which include administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a deuterated analog of any of the above; or a pharmaceutical composition described herein, to a patient, such as a human, wherein said patient has cystic fibrosis3. In some embodiments of the invention, the patient has the E5Ovaeii/minimal function (ME) genotype

EB5ovayeug5ovaye! (homozygous for EBovaei mutation), E5Ovaei genotype/modulation or genotype

E5 is the residual function (KE). In some embodiments of the invention, the patient is homozygous and contains a single E5ovaea mutation.

In this context, "minimum function (ME) mutations" refer to CETE gene mutations associated with minimal CETE function (virtually non-functional CETE protein) and include, for example, mutations associated with severe defects in the ability of the CETC channel to open and close , known as defective channel modulation or "modulation mutations"; mutations associated with serious defects in cellular processing of SETK and its delivery to the cell surface; mutations associated with the absence (or minimal) synthesis

SETE; and mutations associated with severe channel conduction defects. Table C below includes a non-exclusive list of CETC minimal-function mutations that can be detected by an EUOA-approved genotyping assay. In some embodiments, a mutation is considered to be an ME mutation if it meets at least 1 of the following 2 criteria: the biological plausibility of the absence of a translated protein (the genetic sequence suggests a complete absence of the CETK protein), or IP testing that confirms a lack of response to Compound Ii, Compound X, or the combination of compound I and compound I, as well as population-based evidence of clinical severity (as reported in large patient registries).

In some embodiments of the invention, the minimal functional mutations are those that result in the CETK protein being virtually non-functional and unresponsive to compound HER, compound HER, or a combination of compound HER and compound PI.

In some embodiments of the invention, the minimal functional mutations are those that do not respond strongly to compound II, compound III, or a combination of compound III and compound PS. In some embodiments of the invention, the minimal functional mutations are mutations based on IP migo testing that meet the following criteria in IP migo experiments: baseline chloride transport that was 10 95 of wild-type SETEK and an increase in chloride transport of 10 95 in compared with the initial level after adding compound II, compound II or compound P/compound III to the analysis.

In some embodiments, patients with at least one minimal functional mutation show evidence of clinical severity, defined as: mean sweat chloride » 86 mmol/L, and prevalence of pancreatic insufficiency (PN) » 50 95.

Patients with the E5Oovae/minimal function genotype are defined as patients who are heterozygous for E5oOvae!I-CETC with the second allele of CETC containing a minimal function mutation. In some embodiments, patients with the E5Ovaeii/minimal function genotype are patients who are heterozygous for E508aee!I-CETC with a second allele of CETEC containing a mutation that results in the production of a CETE protein with minimal CETE function (functional

SETC is practically absent) and which does not react strongly to compound II, compound I, or a combination of compound II and compound PP.

In some embodiments, minimal functional mutations can be determined using From primary sources: the biological probability of a mutation response (e.g., mutation class) population-based evidence of clinical severity (according to the CETK2 patient registry; as of February 15, 2016) the mean chloride in sweat » 86 mmol/l, and the prevalence of pancreatic insufficiency (IP)» 50 95 testing IP migo mutations leading to chloride transport output «1095 wild-type CETC were considered to be minimal function mutations leading to chloride transport «10 956 wild-type CETC after addition of compound II and/or compound III were considered insensitive.

As used herein, the term "residual function mutation" refers to class II-M mutations that have some residual chloride transport and result in a less severe clinical phenotype. Mutations of residual function are mutations in the SETK gene that lead to a decrease in the amount or function of the protein on the cell surface, which can cause partial activity of SET A.

Non-limiting examples of SETK gene mutations known to result in a residual function phenotype include a residual function SETK mutation selected from 2789-50-5A, 3849-410K60-T, 3272-26A-0, 711-3A-0 , EB5bK, RB7Y, V74MU, 0110, OI1TON,

В117С, 1206МУ, 8347Н, 3520, АЯ55Е, 05790, ЕВЗИХ, 59451, 5977Е, Е1052У, В107ОМУ, Е10741, 01152Н, 01270М, Е193К and К1060Т. For example, CETE mutations that cause defective mRNA splicing, such as 2789-507, result in reduced protein synthesis but deliver some functional CETE to the cell surface to provide residual function. Other CETE mutations that reduce conductance and disrupt the gating mechanism, such as K117H, result in a normal number of CETE channels on the cell surface, but the functional level is low, resulting in residual function. In some embodiments of the invention, the mutation of the residual SET function is selected from K117H, 51235K, I1027T, Nbb68C,

Ca576A, M47OU, I 997E, 8750, 10700, VZ1C, 061402, 10698, 811621, E5bK, A1067T, E19ZK and

K1060T. In some embodiments of the invention, the mutation of the residual function of CETE is selected from

В117Н, 51235Н, И1027Т, 86680, 2576А, МА7ОМ, И 997Е, 750, 810700, ВЗ31С, 06140, 210698,

K1162I, E56K and A1067T.

Residual SET function can be characterized at the cellular (ip migo) level using cell-based assays such as the ECT assay (Map soog, RE. ei ai. (2009) RMABZ Moi. 106,

Mo. 44, 18825-18830; ii Map Soog, R. ei aYi. (2011) RMAB5 My. 108, Mo. 46, 18843-18846) to measure the amount of chloride transport through mutated CETC channels. Mutations of the residual function lead to a decrease, but not to the complete elimination of SETK-dependent ion transport. In some embodiments, mutations in the residual function result in reduced activity

CETC is at least about 10 95 in the ECT assay. In some embodiments, mutations of the residual function lead to a decrease in CETE activity by about 90 95 in the ECT assay.

Patients with the EB5ovaevei/residual function genotype are defined as patients who are heterozygous for E508ae!-SETK with the second allele of SETKE, which contains a mutation that results in a decrease in the amount or function of the protein on the cell surface, which can cause partial activity of SETEK.

Patients with the genotype of the EBoOvaemodulation mutation are defined as patients who are heterozygous for E5ovaei-CETC with the second allele of CETC, which contains a mutation associated with

Defective in modulation and clinically demonstrated to be sensitive to compound I. Examples of such mutations include: 5178, 5549M, 5549K, 55510, 55515, 51244E, 51251M, 51255P, and siaz3490.

In some embodiments of the invention, the methods of treating, alleviating, or symptomatically treating cystic fibrosis disclosed herein independently of each other result in an increase in chloride transport above the baseline level of chloride transport in the patient.

In some embodiments of the invention, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient is heterozygous for E5ov8vaviei and the other CETK genetic mutation is any CE-causing mutation. In some embodiments of the invention, the patient is heterozygous for E5 and the other CETC genetic mutation is any mutation that causes CE and is expected to be and/or responsive to any of the novel compounds disclosed herein, such as compound of formula (I), compound Ii, compound I and/or compound IM of genotypes based on IP data and/or clinical data. In some embodiments of the invention, the patient is heterozygous for E508ae and the other CETC genetic mutation is any mutation that causes CE and is expected to be and/or responsive to any combination(s) of the novel compounds disclosed herein. , such as the compound of formula (I) and (its) compound I! and/or compound I, and/or compound IM of genotypes based on IP miigo data and/or clinical data.

In some embodiments, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has a CETC genetic mutation selected from any of the mutations in Table A.

Table A

Mutations SE nn, against oh ee cha

VE 01000000 | 1898416-A Sova i: nn SHE m p sy nn

Sava 0000000 rivzavit ot5addviya o16i14viS 00000000 p1i9aviA gad

SizizYaeit 00008596 | manual wine now nn shi shi u igmvavzA ST 2788555-A .1249-15-3A o si18884165A opade "12423 o ti8984163s y. - --------- nin p pa V All 1258ip5A o 1a89833A6 00 days and | in 2568ip55 i iovvtA 00000000 189856 shin nya sha p p NN s 1341215-A o r1924der?

MN Pn o o 2 00 ZVO ZA ptdyaatA 0000 20550ei9-3A o ShSh02020----- rza7 med SO Do lo 2 z9V1avi33 tdduavivvv 11111111 12105-21174811ZZABADA 0000000 in PP vovtanyu : 4 0000 zPIz40231 August 4 2018

A OT1VzAAOya 001 Zobip5A

Atlas on V PO 1609de| SA at 2183 see you at tadedudo t

O1B7YANA | З153двидАо овимявА 0000 л171665/А о г2184двид пышу вује нін рінн нн нн нн нн ння пініnedededededededed VUVAZA (000 3121-977 34995248

Ge 0001 2307p5A 0 deiz5i5

OS NN in nn I mon pi NI pln (| zizaceito

PZV VAV at 12556ip5AT opdaddvia and at 2585deii 1 tu7zavis

CM 010 tva

Table A (continuation) of the number of renewals 00000000 GDOBIOA 00000000 АЮ 000

For dewdens, the nd ndst and nn o u t ovve-Zbbivto 00000100 Droztottaa 01 Guiazue 00000000000000000000ODIA AZ79INA ABIZTS C6B7IP500 00

DEC o U Dvi shA 0000000 ABB1E zvaaMoKes-yat dNA 000000 s276X

ZVO A 00000000 ГА5ЯТАТОО000000 sz24k vdo your 1 sS52ah rutu chna nn st in Setkdeg, Z penya 000 En SETNOeiv22-23 z7bivid 5 Popa rutu chan 6213163 roe

Zea Vzuzhnaya Nur Nin NN C NN 3905IPP VOZEEIT NSHNETITT VESVITT VISVIT ARI7S BB A 1548D8I5 19360000 D00542T-XS

Ї 711156-3А рогам 4016бін5т и ииииииииийийий шпнтниитнитнинитинийини ння 712-16-51 ве79у пнннннненнннннннннннннннння 7т к1104Х а040деїА ПИ ПОН ПОКХн ниття 852де122 ЕІ 405416-А ПОМ ПН ПО ння 935деЇА гі371Х 4052-3А-С М пити 991де15 Е193К

Table A (continued) вЕИВ3Х 00000000 M as 2223 ВЕ 000000 pizevM

ECO 0 ex at 000000 g vam 000 anu s: vam pek INNA ak 000000 vkh 00000000 at 0000000

EX 00 BIV 0000 avozyae 00000 azh vii ad ko 00 va 0 I6O1E pe | sao | IMAGINE 0000 au ya wa Gu

OV g now I

SEBOvan 000 vyk I1065R pln av ayt 000 via 00 dev repu: I rak 3 au ese via en ik: M vva p: nn i218X

Table A (continued) n; nn ee: oovnshv byu 00000000 Hashyph oovizn pah 00000000 d22oh | | K117R 1867R i 00 | Vi283M pav 00000000 az o kizvzv kn da52R | Suiton only p29oh | "kovo kl azeh | | vz1 kl 414 | vzzai as much as 00000000 ol1ah | "83340 we! 00000 EBVYAH | "vzzam mish o Z splezh | svzatn miv 00000000 О525Х vzat mit Z а552х | | 8347Р

MmiIM | oBya5X | k3520, have av vza have 00000000 ovaoh | oya5i6o me; 00000000 pov | | 5530 met 00000000 pojah | Without in vi06BN | | v5vo5 saliva vdm 00000000 /kBeOt seni v1i0700 | -veBvs clay uch | vTo9X si vi102x | | yati aa 00000000 я1158Х | ovI5y. ap 00000000 vi182 | | on av vy162x | May with B117C oortvakh g O01313X | 00 hours

Table A (continued) vah 00000050 pvvayaE mi2405 | uz pEdBE t mm ke: ny

ET sha | wow

EN ah will enter 000000 578 : where UuvABh age your t me ma I EE

In some embodiments, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has a CETE genetic mutation selected from 5178, 55515, 5970K, 51244E, 51255P, 513490, 5549M, 5549, 51251M, E19ZK,

T1OO52M, T10O698, B117C, B11on, A347N, AZ3520, EBBK, RB7y, I206MU, A455E, 05790, 512358, 59451, VI1070-5-5-10-70, 01270, 01270 10-5A,

Zo

1898--122-»A, 711-10-57, 2622410-5A, 405--4102-»A, 406-10-5A, 4005--10-»A, 1812-10-5A, 1525-10- »А, 712-10-57, 12484-410-5А, 13414-10-5А, 3121-10-5А, 43744-104-5Т, 3850-10-5А, 2789-5(1:- »А, 3849 -410К60-5й, 3272-26А-50, 711-50-5А, 31200-»5А, 1811-1.6КрА-50, 711-3А-50, 1898--3А-50, 1717-80-»А, 1342 -2A-»b, 405--3A-»50, 1716S/A, 1811-10-50, 1898-52-21, 3850-31- »a, IM51460-50-»A, 1898-12-51, 4005-21-50, 621-3a-50, 1949ae184, 3141ae19, C3195aei6, 319996, C3905IP5tt, 4209toa111- ”A, ATO0O6E, AT120T, A2340, AZ40, ABOZ4A , ET116K, E4030O, E474K, E588U, EbOK, E822K, E10165,

E10991, ET91M, EZ1taei, E311I, P508S, E575U, 210618, p12498, Cs1260, 21498, p1948, C194M, see7V, 2a314E, p458U, 2463, 2480C, 26220, 26282, 26289, ab9, ab9, 8, ab-1, NI1O540,

NITO85R, NITO85N, NI1I375R, NIZ398, NI998, NbOZA, NOZON, 11005Н, I1234М, I1269М, 11366М, 1175,

IBO2T, I5065, I5O6T, IbOT R, I6E18T, IVO7M, IZVOK, I 1028, I 1324R, I 1335R, I 138ipo, I 1480R, 1 15R,

Y1655, I 320U, I 346P, 14535, I 5715, 19675, M11018, M152U, MIT, MIM, M265N8, M952I, M952T,

РБ74Н, РБИ, Р7БОИ, ROZI, О1100Р, О1291Н, 012918, 0237Е, О237Н, 0452Р, 0988, В1066С,

WTO6BN, 8117, 81171, B117, B1283m, B12835, B17ON, B2582, Vase, VZ3341, 83340, VZB, VZB52M, 5160, 85530, 87511, 87511 , 5549A(T-20), 5589M, 5737, 59121, T1036M, T1053I, T1246I, T604I, M1153E, M12400, M1293.,

М201М, М2320, М456А, М456Р, У562И, МУ1098С, МУ10988, М/12828, М/З61В, МУ57с, М/57В, 10140, М10320, У109М, М1610, 1615, М5630, У563М, У569С and 913.

In some embodiments, the patient has at least one combination of mutations selected from: 5178K, 55515, (5970K, 51244E, 51255P, 513490, 5549M, 5549, 51251M, E193ZK,

T1OO52MU, 10698, B117C, B11on, 8347n, AZ3520, EBBK, RB7y, I206MU, AY455E, 05790, 512358, 59451, VI1070, E1074, 0127 10-5А, 1898--122-»А, 711-10-57, 2622410-5А, 405--4102-»А, 406--10-5А, 4005--10-»А, 1812-10-5А, 1525-10-»А, 712-10-57, 12484-410-5А, 13414-10-5А, 3121-10-5А, 43744-104-5Т, 3850-10-5А, 2789-5(1:- »А, 3849-410К60-5й, 3272-26А-50, 711-50-5А, 31200-»5А, 1811-1.6КрА-50, 711-3А-50, 1898--3А-50, 1717-80- »A, 1342-2A-»b, 405--3A-»50, 1716S/A, 1811-10-50, 1898-52-21, 3850-31-a, IM514r--50-»A, 1898- 10-57, 4005421-»2С and 621 43А-50х.

In some embodiments of the invention, the patient has at least one combination of mutations selected from: 1949deI84, 3141de19, 3195adei!b, 3199de1I6, 3905Ip57, 42097 1T-5A, ATO0O6E, A120T,

Зо А2340, АЗ49М, АбИЗТ, Сб5248, р1920, р443у, р5130, р836М, 0924М, 0979У, Е116К, Е4О0З0,

E474K, E588U, EBOK, EV22K, E10165, E10991, E191M, Ez1Taei, Ez111, E508C, G575U, 210618, C Plga, C1260, 21498, C1948, C1948 sv2gvv(a-»A), 2918, 19700, НИ10540, НИО85Р, НИО858, НИ375Р, НИЗ39В, НИ99В, НбОЗВ, НОЗОВ,

ITOO5B, IT1234U, I1269M, I1Z366M, 1175M, I5O2T, 15065, I5BOBT, IbOTE, IE18T, IVO7M, IZ8OK, 11028,

ИЙ1324Р, 11335Р, И 138ip5, И 1480Р, 115Р, 11655, И Z2ОМ, 1346Р, 14535, 15715, 19675, М11018,

M152U, MIT, MIM, M265N8, M952I, M952T, RB74N, RBI, R7BOY, ROO9I, О1100Р, 0О1291Н, 012918,

О237Е, 0237Н, 0452Р, 0988, В8Т066С, ВТ1О66Н, А1170, А1171, В117Р, В1283М, В12835,

B17О0Н, B2582, VZ1I, 83341, 83340, 3471, VZ52MU, 5160, 85530, 87911, 7920, VOZZa,

Z1118B, 51159B, 51159Р, 513, 5549Н(А-50), 55498(Т-50), 5589М, 5737, 59121, Т1ОЗ6М,

T1053I, T12461I, T604I, M1153E, M12400, M12930, M2O1M, M2320, M456A, M456E, U562I, M/10980,

МУ10988, М/12828, МУЗбИВ, М/57Сс, МУ57В, М10140, М10320, М109М, М1610, М1615, М5630,

U563M, U569C and 9136.

In some embodiments, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has the CETC genetic mutation 05510. In some embodiments, the patient is homozygous for genetic mutation 55510. In some embodiments, the patient is heterozygous for genetic mutation (055510. In some embodiments of the invention, the patient is heterozygous for the 55510 genetic mutation, having the 55510 mutation on one allele and any other CF-causing mutation on the other allele. In some embodiments of the invention, the patient is heterozygous for the 55510 genetic mutation on one allele, and the other genetic mutation causing CE on the other allele is any one of E5Oovaeeii, 5542X, M1ZOZK, M/1282X, K117N,

В55ЖХ, 1717-10-5А, 621-10-51, 2789-50-5А, 3849-10К60-5Т, В1162Х, С85Е, 3120-120-»5А,

AI507, 1898--105-5A, 3659de!S, B8347R, A56OT, AZZAMU, A455E, 2184deiA or 711410-»T. In some embodiments of the invention, the patient is heterozygous for the genetic mutation (5510) and the other genetic mutation of SETE is E5O8ae. In some embodiments of the invention, the patient is heterozygous for the genetic mutation 55510 and the other genetic mutation of SETE is K117H.

In some embodiments of the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has a CETC genetic mutation

E508deI. In some embodiments of the invention, the patient is homozygous for the E5OvaeI genetic bo mutation. In some embodiments of the invention, the patient is heterozygous for the E5Bovaee genetic mutation, where the patient has the E5ov8aee genetic mutation on one allele and any CF-causing genetic mutation on the other allele. In some embodiments of the invention, the patient is heterozygous for E5ovae and the other SET genetic mutation is any CE-causing mutation, including, but not limited to, 55510, (3542X, M13OZK,

М/1282Х, В117Н, В55Х, 1717-10-5А, 621-10-51, 2789-50-»5А, 3849-10K60-5Т, В1162Х, С85Е, 3120-102-»А, ЛИБ0О7, 1898410-»А , 36594eIS, KZ347R, K5bOT, K334MU, A455E, 2184deiA or 711--10-2T. In some embodiments, the patient is heterozygous for E5ovavei and the other genetic mutation of SETK is (35510. In some embodiments, the patient is heterozygous for E5ovavei and the other genetic mutation of SETK is K117H.

In some embodiments of the invention, the patient has at least one combination of mutations selected from: p443y: (a576A; Ab66B8C,

E508C;:51251M, p576A; Nbb6VS, 29708; M47OU, v7a4MgO127ОМ,

ETAMGM2O1M, and in74MM201mM;0127OM.

In some embodiments, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has a CETK genetic mutation selected from C178K, 55515, 5970, 51244E, 51255P, 0513490, 5549M, 55491, 51251M, E19ZK,

E1052M and 510694. In some embodiments of the invention, the patient has a genetic mutation

CETE selected from C178K, 55515, 5970, 51244E, 51255P, 513490, 5549M, 554912 and 51251M. In some embodiments of the invention, the patient has a CETE genetic mutation selected from E19ZK,

E1052U and 51069K. In some embodiments, the method results in an increase in chloride transport compared to the baseline level of chloride transport in the patient.

In some embodiments of the invention, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has a SETEK genetic mutation selected from the following:

From 81070, 210741, 011ОЕ, 01270М and 01152Н.

In some embodiments, the patient has a CETE genetic mutation selected from 1717-10-5A, 621-10-57, 3120-120-5A, 18984-120-5A, 711-10-57, 2622--120-»5A 405-10-5А 410-5А, 3121-105-»А, 4374410-5Т, 3850-10-5А, 2789--50-х:А, 3849-10К00-5Т, 3272-26А-»50, 711-50-5А, 31200 - »А, 1811-1.6КБА-»0, 711--3А-50, 1898-4-3А-»01, 1717-80-»А, 1342-2А-»0, 4055-3А-50, 1716С0/ A, 1811-10-20, 1898--505-5T, 3850-3T-20, IM514r--502-»A, 1898--41023-»5T, 4005-21-2С and 6213А-26. In some embodiments of the invention, the patient has a CETE genetic mutation selected from 1717-10-»A, 1811--41.6KrA-x0, 2789--50-2A, 3272-26A-»5 and 3849410KrOS-»T. In some embodiments of the invention, the patient has a CETE genetic mutation selected from 2789450-»A and 3272-26A-»0.

In some embodiments, in the methods of treating, alleviating, or symptomatic treatment of cystic fibrosis described herein, the patient has a SETEK genetic mutation selected from C178K, 55515, 5970, 51244E, 51255Р, 213490, 5549M, 55498, 51251M, E19ZK,

T1OO52M, T10O698, B117C, B11on, A347N, AZ3520, EBBK, RB7y, I206MU, A455E, 05790, 512358, 59451, VI1070-5-17, 0120, 0127 10-5А, 1898--122-»А, 711-10-57, 2622410-5А, 405--4102-»А, 406--10-5А, 4005--10-»А, 1812-10-5А, 1525-10-»А, 712-10-57, 12484-410-5А, 13414-10-5А, 3121-10-5А, 43744-104-5Т, 3850-10-5А, 2789-5(1:- »А, 3849-410К60-5й, 3272-26А-50, 711-50-5А, 31200-»5А, 1811-1.6КрА-50, 711-3А-50, 1898--3А-50, 1717-80- »A, 1342-2A-»b, 405--3A-»50, 1716S/A, 1811-10-50, 1898-52-21, 3850-31- »a, IM514r4502-»A, 1898-4- 10-»5T, 4005421-»C and 62143A-»b, and human CETE mutations selected from

E5ovaei, K117N and 05510.

In some embodiments, in the methods of treating, alleviating, or symptomatically treating cystic fibrosis described herein, the patient has a CETK genetic mutation selected from C178K, 55515, 5970, 51244E, 51255P, 513490, 5549M, 55491, 51251M, E193ZK,

T1OO52M, T10O698, B117C, B11on, A347N, AZ3520, EBBK, RB7y, I206MU, A455E, 05790, 512358, 59451, B1070-17, 010, 0127 10-5А, 1898--122-»А, 711-10-57, 2622410-5А, 405--4102-»А, 406--10-5А, 4005--10-»А, 1812-10-5А, 1525-10-»А, 712-10-57, 12484-410-5А, 13414-10-5А, 3121-10-5А, 43744-104-5Т, 3850-10-5А, 2789-5(1:- »А, 3849-410Кр0-5й1, 3272-26А-50, 711-50-5А, 31200-»5А, 1811-1.6КрА-50, 711-3А-50, 1898--3А-50, 1717-80- »А, 1342-2А-»б, 405--3А-»50, 1716С/А, 1811-10-50, 1898-52-21, 3850-31-

a, IM5146B--50-5A, 1898-10-57, 4005--2T1-»2C and 62143A-»0, and the CETE mutation selected from E5Oovaei,

K117H and 65510; and CETE mutations selected from E5Oovaeii, K117H and 55510.

In some embodiments, the patient has a CETE genetic mutation selected from se1788, 25515, 29708, c1244E, 51255P, 13490, 5549M, 5549K, 51251M, E19Z3K, E1052M and

C1069K, and a human CETE mutation selected from E5Oova, K117H, and 55510. In some embodiments, the patient has a CETE genetic mutation selected from 5178, 55515, 5970K, 01244E, 51255P, 513490, 5549M, 55491, and 51251M, and a human CETE mutation , selected from

E5ovayi, K117H and 55510. In some embodiments of the invention, the patient has a CETE genetic mutation selected from E19Z3K, E1052M and 51069, and a human CETC mutation selected from

EB5Oovaeei, K117N and 65510.

In some embodiments of the invention, the patient has a CETK genetic mutation selected from

B117C, RYTON, VZ347N, AZ3520, EB5bK, RbB7/, I 206MU, A455E, 057920, 512358, 59451, B107ОМУ,

E10741, B11OeE, 01270M and 01152H, and a human CETE mutation selected from E50vae, K117H and a5510.

In some embodiments, the patient has a CETE genetic mutation selected from 1717-10-5A, 621-10-57, 3120-120-5A, 18984-120-5A, 711-10-57, 2622--120-»5A 405-10-5А 410-5А, 3121-105-»А, 4374410-5Т, 3850-10-5А, 2789--50-х:А, 3849-10К00-5Т, 3272-26А-»50, 711-50-5А, 31200 - »А, 1811-1.6КБА-»0, 711--3А-50, 1898-4-3А-»01, 1717-80-»А, 1342-2А-»0, 4055-3А-50, 1716С0/ A, 1811-10-50, 1898--503-5T, 3850-3T-20, IM514r--502-»A, 1898--124-5T, 4005421-»2C and 6213A-50, and a mutation of human SETE, selected from E5Oovaeii, K117H and 55510. In some embodiments of the invention, the patient has a genetic mutation of CETC selected from 1717-10-5A, 1811-41,6KrA-:a, 2789-50-»A, 3272-26A-»05 and 3849410KrOS-»T, and a human CETE mutation selected from E5ovavea,

B117H and 55510. In some embodiments of the invention, the patient has a SETEK genetic mutation selected from 2789450-»A and 3272-26A-»0, and a human CETE mutation selected from E5Oovaeyi, K117H.

In some embodiments of the invention, the patient is heterozygous and has a CF-causing mutation on one allele and a CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for E5ova and the other CETC genetic mutation is any CF-causing mutation, including, but not limited to, E50eva on one allele of CETC and a mutation

From SETK on the second SETK allele, which is associated with minimal SETK function, residual SETK function, or a defect in the modulation activity of the SETK channel. In some embodiments, the CE-causing mutation is selected from Table A. In some embodiments, the CE-causing mutation is selected from Table B. In some embodiments, the CE-causing mutation is selected from Table C. In some embodiments, the CE-causing mutation is selected from Table C. in embodiments of the invention, the mutation causing CE is selected from Fig. 2. In some embodiments of the invention, the patient is heterozygous and has a CE-causing mutation on one allele

CETE selected from the mutations listed in the table in Fig. 2 and the CE-causing mutation on the other SETK allele is selected from the SETK mutations listed in Table B:

Table B

Mutations of SETK oh B1104X 10785asIit

ZX K158X 1p1548TS

EBsoh kpeOohX 21853de1AA-o

VlZh zp1196X 2143deIIi

E92X MZH1204X 1677481TA

OKH 512535X 3876421 A

У122Хх Ж1282Х 230 лп5А 1218Хх ОИЗИ3ХХ 4382414 о22оХ 621-410-Т 4016151

С276Хх p1-10-T 2347dei6 09290Х 71150-А 30078216 szzoХ 712-10-Т 574dgiA tu491хХ 405410-А 2711deit

Ох 4053А-С 37914сИС зазах 406-И0-А SETtKasig22-23 зи66х 621410-5-Т 457TAT-о 5А8ОХ 124816 А 2045de16

О493Х 13411С5--А 2869180 ту496хХ 1717-10-А 3600121а5Т

О0525Х 1811-51 6КВА--О 3737421 а542Х I niv-S zo4odei 0552Х 1812-16-5А ас

KUZH IV A dABO 338 вх 262210-А TAZVI obh В347Р 3120Н10-А k7оХ 1927Р 31200-А koh С8ЗЕ 3850-10-А 179Х 5341Р 40055160-А k7AK I467рР 437410-Т kah 2 15074

Kk792X UZ 2183АА-О

BEH A559UT

SETtVaei2,3 chUVabH cat ze59deIS

K8UiH K5bo5 zooadentT Y two and AZO1E 2184t8A 5IH U5690 39051157

ЖМ1о89Х 11065Р 21844гА Shch

U1092X kI0boS

Table B (continued)

В1066М 11077Р no

Mpa

MIZOZK z849-10КС-Т 3272-26А-а

L1A-O

EBC

ROLE,

KklaAzhm rPov ryn

B117s t206Uu vza7n k3520

ADM root

B83IX 5944, 5977E

E1052U

Viotok

E1074Y, ry52n ri27oM juice 5Z4ZM 5549K

Secondary school

05515 01244 51251М 51255Р ai3490

Table C

Mutations of SETK

Criteria Mutation

Truncated mutations ah shh oh3h ntIh vinyh "a RI" Mu halo SOTHh s29ah azh KyalIh vyh zasyabymollo sDoH azih OH evaBH vyh " no xx zkaaihH k553H chah yaoeh povnorijyurnyh vah sonyah EZNyaH VH zah proteins nu palah sec uperta u vlahh ztsach satUh oh yahh

ЭХ «ех сОехах НХ візчх о9ах шавох влюх ох хИз82Х чУиМх гпМаозхХ ЭХ uzohoh sizіzh

КИЗХ зкаовХ лох ХюХ влих

I218X sah tah IOEH. pIZH so sa5h vkoyaah ViNnshHh sih

Stnnanoyemutavii inn 1 5-nnA 01717504 A zad un Z --»A . zu VI» 3055 tyadaobo ZOBA OTI2-G 01 -A IN nn ZNYU- Anya

ALL min mmol o ZOO A BDYAVNYA 18 NIS zano zodvezivni " vemayeor little mature Z053A--y 1240-10-93 A 111 YABoA-MI 0 (O97OB) ZYA830-1 OA chik slohy zchafazih ge z z zad A

BUT 13-X 1512 MA M NI-A candle 1528-3А- 0 198 О--А, ZI О-А UT rea RIV A 0 1VOVRONS 3121-3А--о

Small (Zo RE2aYAT NizalA itaanaA 2732 Z876asiaA of muklestids: mutashchiyi ZOBA. NNI 1524 aA zkevonM zktyaaeni of framekvouttuvlnia shift Zoya animals and cuts 0 s04adeyu Hob zaoyashhi with the insertion of BOTI n pora duilat prin ot

Y oz Mvicheyut zI4laeii zara Z01biphihi delepiya (pali 114 shchi y Da Di zasaaA 12134 MIBZAA-NOI zo574asii 402idavri "a RIZ MI puabo s. Sh y

For A BIUakhA Zika anA zate KNOYAA yah ho mmol 000 887TAT--O OVVNyeTA 0 l1b4atkA zo2vasiaA Zatv

Ж r vorenyi tagaiyu pon zate zateidei a3yttA zi z3364e S ustisnNcn solo ztafid iaotaenki 0 oza7aeyu zezudaeiS veze Ihavaeyu z5khaeIt zate ozkhiasiA zakuesA 0 z5oaieYUT zom tova ivtnenA 0 z71aeY zva

Circulating 3 SETs, which ones are for aevo nucleotides) or mutated SET Vae2323 io? Wetlivzy shift of the chewing frame of the back zv55ysi - And we will bring it to the votankoua MO ssh and pi nia

I and 7ovyaoI z105- AMYUTST-AA

Coll

Table C (continued) banner 000000 Mu 00000000 dele blyudi z17asn pazASAAA, -e b RIZE WHAT» zhdiaioa o 55102)5 pt3a1dgi hg hv mmol l « spoinorenvy galabo haichenyi imlak

Zhvatevy 000000 MiayauD 00000000

OMavy batter. SHOW. AB О0000бяюр 000 Already 00000 МАНКО00000 which do not correspond to the indications of the regulations5 of use separately bot ruatr VN be homineae with connected g457tr: nivoh tIiattv»

M or kpadukoayu GU and SHY and . and tabtagi AZAE myteE "5 RE OK; srudbeo vek sr Bo mmelsi

The same does not react with TE compounds separately when combined with a Mo compound or a GU compound

Note. 95 RI: percentage of heterozygous for E5ov8aee!I-SETK patients in the registry of patients with

CETK2, who have pancreatic insufficiency; ZmM/SI -: the average indicator of sweat chlorides of patients heterozygous for E5Oovaee!I-SETE in the SETK2 patient registry and Also known as 2183deIAA--0. r Unpublished data.

In some embodiments of the invention, the patient: with genotypes gE50vaeimeE (P/ME) (heterozygous for E508ave and an ME mutation that does not respond to SETEK modulators, such as a compound

IP); with genotype E5ovaeie5ovaei (B/R) (homozygous for E5ovaei); and/or with genotypes

E5Ovae!/modulation (E/) (heterozygous for E5o8aei and a modulation mutation known to be sensitive to a CETC modulator (eg, sensitive to compound II). In some embodiments, a patient with EB5OovaeimME (B/ME) genotypes has a mutation ME that is expected to fail to respond to Compound I, Compound PI, and Compound II and Compound PP In some embodiments, a patient with EBZOovaeimE (P/ME) genotypes has one of the ME mutations listed in Table C.

In some embodiments, the patient is heterozygous for EBovaei and the other CETC genetic mutation is any CF-causing mutation, including truncation mutations, splicing mutations, small (x 3 nucleotides) frameshift mutations with insertion or deletion (ipv/dei ); large (7 C nucleotides) frameshift mutations with insertion or deletion (ipz/aei); and class II, PI, IM mutations that do not respond to compound I alone or in combination with compound II or compound IM.

In some embodiments, the patient is heterozygous for EBova and the other CETC genetic mutation is a truncation mutation. In some specific embodiments, the truncation mutation is a truncation mutation listed in Table C.

In some embodiments, the patient is heterozygous for EBovaei and the other CETC genetic mutation is a splicing mutation. In some specific embodiments, the splicing mutation is a splicing mutation listed in Table C.

In some embodiments of the invention, the patient is heterozygous for EB5ovaei, and the other genetic mutation of CETK is a small (x3 nucleotide) insertion or deletion (ip5/dei) of a frameshift mutation. In some specific embodiments, the small (`3 nucleotide) insertion or deletion frameshift mutation (ip5/deI) is a small (`3 nucleotide) insertion or deletion frameshift mutation (ip5/deI) listed in Table C .

In some embodiments, the compounds of Formula (I), (1I-A), (1-8), (PI-A), (PI-B), (IM-A), (IM-B), (IM-

C), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-U) and their pharmaceutically acceptable salts and deuterated derivatives, the patient is heterozygous for E508ae, and the other CETC genetic mutation is any CF-causing mutation expected to be and/or responsive, based on immunological and/or clinical data, to any combination(s) of the novel compound selected of those disclosed in this document (for example, compounds of formulas (I), (1I-A), (P-B), (PI-A), (PI-B), (IM-A), (IM-B), (IM-C), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-O) and their pharmaceutically acceptable salts and deuterated derivatives) , and (its) Compound II and/or Compound II and/or Compound IM.

In some embodiments of the invention, the patient is heterozygous for E5ovaei and the other SETEK genetic mutation is any CE-causing mutation that is expected to be and/or is sensitive, based on immunological and/or clinical data, to the triple a combination of a new compound selected from those disclosed herein (eg, a derivative) and compound II and compound PP.

In some embodiments of the invention, the patient is heterozygous for EB5ovaei, and the other genetic mutation of CETC is a large (» C nucleotide) insertion or deletion (ip5/dei) frameshift mutation. In some specific embodiments, a large (» C nucleotide) insertion or deletion frameshift mutation (ip5/deI) is a large (» C nucleotide) insertion or deletion frameshift mutation (ip5/deI) listed in Table C.

In some embodiments, the patient is heterozygous for EBovaei and the other CETC genetic mutation is a class II, IS, IM mutation that does not respond to compound PS alone or in combination with compound II or compound IM. In some specific embodiments, mutations of class II, SH, IM, which do not respond to compound IP alone or in combination with compound I! or compound IM, are mutations of class ІІ, PI, IM, which do not respond to compound IP alone or in combination with compound II or compound IM, listed in table C.

In some embodiments, the patient is heterozygous for EBova and the other CETE genetic mutation is any mutation listed in Table C.

In some embodiments, the patient is heterozygous for E5ov8aee and the other CETE genetic mutation is any mutation other than E5o08aee listed in Tables A, B, C, and

Koo) fig. 2.

In some embodiments, the patient is heterozygous for EB and the other SET genetic mutation is any mutation listed in Table A. In some embodiments, the patient is heterozygous for E5 and the other SETC genetic mutation is any mutation listed in Table B. In some embodiments, the patient is heterozygous for E5Oov8ae and the other CETC genetic mutation is any mutation listed in Table C. In some embodiments, the patient is heterozygous for E5ov8ae and the other CETE genetic mutation is any of which mutation indicated in fig. 2.

In some embodiments of the invention, the patient is homozygous for E5ovavei.

In some embodiments of the invention, the patient is heterozygous and has one CF-causing mutation on one CETE allele selected from the mutations listed in the table in FIG. 2 and another CF-causing mutation on a different SETE allele. selected from the CETC mutations listed in

Tables S.

In some embodiments, the composition disclosed herein is useful for the treatment, amelioration, or symptomatic treatment of cystic fibrosis in patients exhibiting residual CETC activity in the apical membrane of respiratory and non-respiratory epithelium. The presence of residual CETC activity on the epithelial surface can be readily detected using methods known in the art, such as standard electrophysiological, biochemical, or histochemical methods. Such methods determine activity

CETC using ip mimo or ex mimo electrophysiological methods, measurement of Si concentrations in sweat or saliva, or ex mimo biochemical or histochemical methods for monitoring cell surface density. Using such methods, residual activity

CETC can be readily detected in patients who are heterozygous or homozygous for many different mutations, including patients heterozygous for the most common mutation

E5ovaei, as well as other mutations, such as the 55510 mutation or the K117H mutation. In some embodiments, the compositions disclosed herein are suitable for the treatment, mitigation, or symptomatic treatment of cystic fibrosis in patients who exhibit little or no residual CETE activity. In some embodiments, the compositions disclosed herein are suitable for the treatment, mitigation, or symptomatic treatment of cystic fibrosis in patients who exhibit little or no residual CETC activity in the apical membrane of the respiratory epithelium.

In some embodiments, the compositions disclosed herein are suitable for treating or reducing the severity of cystic fibrosis in patients experiencing residual activity

SETC, using pharmacological methods. Such methods increase the amount of CETC present on the cell surface, thereby causing the patient to have previously absent activity

CETE or by increasing the existing level of residual CETC activity in the patient.

In some embodiments, the compositions disclosed herein are useful for treating or reducing the severity of cystic fibrosis in patients with certain genotypes that exhibit residual CETC activity.

In some embodiments, the compositions disclosed herein are useful for treating, ameliorating, or symptomatically treating cystic fibrosis in patients with certain clinical phenotypes, e.g., a mild to moderate clinical phenotype that generally correlates with the amount of residual CETE activity. in the apical membrane of the epithelium.

Such phenotypes include patients with pancreatic insufficiency.

In some embodiments, the compositions disclosed herein are useful for the treatment, palliation, or symptomatic treatment of patients with diagnosed pancreatic insufficiency, idiopathic pancreatitis, and congenital bilateral vas deferens or mild lung disease in which the patient exhibits residual CETC activity .

In some embodiments, the present disclosure relates to a method of increasing or inducing the activity of an ip migo or ip mimo anion channel comprising contacting the channel with a composition disclosed herein. In some embodiments of the invention, the anion channel is a chloride channel or a bicarbonate channel. In some embodiments of the invention, the anion channel is a chloride channel.

In some embodiments of the invention, the patient is heterozygous and has an E5Oov8aeee mutation on one allele and a mutation on the other allele selected from Table 5:

Table 5

Mutations of SETK 5-h Ogoh "shIh EBzaH nah

ХХ UateХх s pah жАКИХ втізаХ sih sah Oh chuvaBH vyh oh s029OHH В533Х Uh oh dah Chchazyh EZVIH vyh minnih

Kooh NIH С73Х spvooh и31254Х vah payah OOBVEH «ah BI25ЭХ

Idyakh zkh vlozhkh Uazkh x12sh2kh

BOIH 5a6vkh koh so10zh2H oizh

OH chaKoH Oh xx OoVoH avizzoh

Уи22х сО493хХ ИЛХ чиваих визих

BIZZH huZoeh. Vloakh lAevyaH OSIZVIH cheh saz2ah lah kiIh ICHIH

Genre 7150-33 А 00 177-Я0-ЗА 0 chapter A ZONE 000000 zvn A OID 1717-0-A ZONE Z500-2A--NO dobeov- vmVniyY--nA OO 1KNNON-NE MenK- S 000 Zh ki zahnNa-A I249-NU A 11 OKVA-NYAO 0 OUN z8shShn10a-A 4053A- 341 50--A 18116430 31200-3A 0 ЯЦ051 А 306-30-А 00 Р528-2А-ЯЯУ 0 1В12- NA diEMnNiby-A 33745 Р5-25T baron -Ka-A 001898 A 3121-38 A-n tina-y ICON orkzayett o 000ot7vaeT 000 67eTA 000 zaA 000000 106 A rea it 2732iv5A ztnagis zoba TANA 135 ikhanievA zbo ZyaZ1aeT 3a5-3b6ii 1545 o ZAezob0 АхЭбой3z3

Table 5 (continued)

Mutations of SETK

Мутація з94деТТ 1161де1С 2043де1й 29421п57Т 3878426 з4а2асіА 1213деї1Т 2143деІіТ 2957деїї 39051251 444дг1А 1259105А 2153АА-С 3007дгіС 40161571 357ТАТ1-с 128505ТА 2154де1А зо28ас«іА 4021ч4ирт 5414гіС 1343де16 2184іп5А зі7іагіС 40221051 574де1А 147140г1А 230ЯпЗА 317НазС 40404е1А вбзагіт 1407д2г160 2347де10ї 3271д210о 4279118А я49агіС 1545дг16 2585деїТ 3349іп«Т 4326дгІТС 9354е1А Ii 609dei SA 25944210 zbh9deiIS

SETtTKagigi SET Kdeie16-17b 14611p54

SETKaviez SETKagivita176 1924de17

SETKavie2,3 SETKagivi17a-18 2035d4e19-А

SETtVdsi2-4 SETKagie19 2105-2117de 1 ZpVASAAA

SEtVagie3-1014r-16 SETKdeiee19-21 23724218

SETtKasgi 4-7 SETtKagezi May 27

SETKasiv 4-11 SET Kaeie 22-24 2991de132

SETAZOKVaeY SET Kdeiee22.23 3bbtpza

SETKaoOreB-10 124de125Br 40104214

SETtTKagisi 60242114 42091111-AA

SETtTKagig13,14a 852d4gi22

SETtKasig14B-17B 991de15 dBI U520E UZ mizo3K

SV A55ZZT 11065R

KAR K5oOG kovo t1467R E5605 11077R 1507dei AVO1E MmpoIKk

The exact amount of pharmaceutical composition required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the disease, the particular agent, the method of administration, etc. The compositions according to this invention can be formulated in the form of a single dosage form for ease of administration and uniformity of dosage.

The term "standard dosage form" as used herein refers to a physically discrete unit of agent suitable for a patient to be treated. However, it should be understood that the general daily use of the compounds and compositions of this disclosure will be decided by the treating physician within the framework of sound medical judgment. The particular effective dose level for any particular patient or organism will depend on many factors, including the disorder being treated and the severity of the disease; the activity of a specific composition used; the specific composition used; age, body weight, general health, gender and diet of the patient; the time of administration, the method of administration and the rate of excretion of the specific compound used; duration of treatment; drugs used in combination or coinciding with the particular compound used, and similar factors well known in medicine. The term "patient" as used herein refers to an animal, such as a mammal, and even more so, such as a human.

In some embodiments, the disclosure includes deuterated derivatives of the novel compounds disclosed herein and pharmaceutically acceptable salts thereof. Non-limiting examples of deuterated compounds are disclosed in FIG. 1.

In some embodiments, Compound P-a used herein includes a deuterated compound disclosed in US Patent No. 8,865,902 (which is incorporated herein by reference) as: (c) c)

NM / NM or or bro

The clinical efficacy of compound PI-4 in combination with other correctors of CETC, including combinations with compound II, was described in Yuamie5 ei aI., Mem/Epoi. U. May. 379(17):1599-1611 (2018) apa Oamiez ei ai., Mem Epai. U. Mea. 379(17):1612-1620 (2018).

Exemplary embodiments of this disclosure include: novel compounds disclosed herein (eg, compounds of formulas (I), (PI-A), (II-B), (PI-A), (PI-B), (IM- A), (IM-B), (IM-C), (M-A), (M-B), (MI-A), (MI-B), (MI-S) and (MI-Y) , their pharmaceutically acceptable salts and deuterated derivatives of any of the above, including the compounds of Fig. 1 and specifically depicted herein), may be prepared by suitable methods known in the art. For example, they can be prepared according to the exemplary compounds described below in the examples. For example, deuterated derivatives of new compounds of formulas (I), (IPI-A), (1-8), (PI-A), (PI-B), (IM-A), (IM-B), (IM- O), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-O) and their pharmaceutically acceptable salts can be obtained in a similar way as and for compounds of formulas (I), (PI-A), (1-8), (PI-A), (PI-B), (IM-A), (IM-B), (IM-C), (M-A), (M-B), (MI-

A), (MI-B), (MI-C) and (MI-O) and their pharmaceutically acceptable salts using intermediates and/or reagents where one or more hydrogen atoms are replaced by deuterium.

For example, see T.0. (zapi "Ovipd deshegpyt ip agid aizsomegu: Ieamipu (Pe Iabei ip (pe agid)," 9. Mea.

Spent 2014, 57, 3595-3611, the relevant parts of which are incorporated herein by reference.

In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts, as well as deuterated derivatives of any of the above, are prepared as shown in Schemes 1-12, wherein each of the variables independently corresponds to the following formulas (AND). Suitable conditions known in the art can be used for each stage depicted in the diagrams. The methods disclosed in this document can be used to obtain compounds of formulas (I), (PI-A), (1-8), (PI-A)U, (PI-B), (IM-A), (IM- B), (IM-C), (M-A), (M-V), (MI-A), (MI-B), (MI-C) and (MI-Y), as well as any compounds presented in table 5 and fig. 1, their salts or deuterated derivatives of any of the above.

In some embodiments, as shown in Scheme 1, the methods include reacting a compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof to form a compound of formula (B), a salt thereof, or a deuterated derivative of any of the following above. The interaction of formula (A) and formula (B) can be carried out in any convenient coupling reaction of a carboxylic acid and a sulfonamide, such as with SOY. In some embodiments, the coupling reaction is carried out in the presence of a base, such as OBO.

Scheme 1.

about h

M

(6) With y

NhM t (ve on o? i 7 --- 10 se ke,

M

(4) her (c) (ka 3 3 o Kf 2 5 (vy ba V) t

What? in") vm 7

J

IN

(pe)d 3 (U)

In some embodiments, as shown in Scheme 2, the methods include deprotection of a compound of formula (U) to form a compound of formula (U-1), a salt thereof, or a deuterated derivative of any of the above. Deprotection of formula (U) can be performed under any suitable deprotection conditions apparent to one skilled in the art, depending on the protecting group K10. In some embodiments, the K10 protecting group is Bos and the deprotection conditions are acidic. In some embodiments, as shown in Scheme 2, the methods include reacting a compound of formula (U-1) to form a compound of formula (1), a salt thereof, or a deuterated derivative of any of the above. The reaction of the formula (U-1) can be carried out with any convenient coupling reaction between an amine and a halogen. In some embodiments, this coupling reaction is carried out in the presence of a base, such as K2CO2.

Scheme 2. about oh

M

(in Z c

M t ---- in. and

Gays

In

Elementary school Va-Zh 2

IN

(ka Ge ( ) o oh (88) I ts U Y U Y

Cody ract inse re U Ne -v x M TA tke y uv zhde ra - o ukh v y A (in Nm 27 and unit. I- (85 F in (in in! J mk (U-1) (9)

In some embodiments, as shown in Scheme C, the methods include reacting a compound of formula (A) or a salt thereof with a compound of formula (B-2) or a salt thereof to form a compound of formula (B-2), a salt thereof, or a deuterated derivative of any which of the above The reaction of formula (A) and formula (8-2) can be carried out in any convenient carboxylic acid-sulfonamide coupling reaction, such as with SOY. In some embodiments, the coupling reaction is carried out in the presence of a base, such as OVI.

Scheme 3

M

2 (5, tsa on sun (V

Fo I

MN B-

KO /

M ISVeRU), (4) s (Ka

Kk Z v (8-2) at o.h

M

5 (in cha (Kl on vm in ISReRU), (Ka (y-2g)

In some embodiments, as shown in Scheme 4, the methods include reacting 10 a compound of formula (0) or a salt thereof with a compound of formula (E-2) or a salt thereof to form a compound of formula (B-2), a salt thereof, or a deuterated derivative of any - any of the above. The reaction of formula (0) and formula (E-2) can be carried out according to any convenient coupling reaction between amine and Ca.

Scheme 4. och 24 uh M rey 10 Mn, N cha (Kt (t) Kk / 2

Nm " t svere a s Y I vo v 10 MN e3 KK / (E-2) M ISReRU, (0) s

Kk 3 and (8-2

In some embodiments, as shown in Scheme 5, the methods include reacting a compound of formula (A) or a salt thereof with a compound of formula (B-3) or a salt thereof to form a compound of formula (B-3), a salt thereof, or a deuterated derivative of any which of the above The reaction of formula (A) and formula (8-3) can be carried out in any convenient carboxylic acid-sulfonamide coupling reaction, such as with SOY. In some embodiments, the coupling reaction is carried out in the presence of a base, such as OVI.

Scheme 5.

oh oh

M

2 Z (5, scha on 7 (v

Fo I would 10 9) sh

KO /

MS ISVOKU, (A) (Kk y Z y (B-3)

Oh oh

M

(2, m? (tu on vm sny ag in ISReRU, (Ka (u-3)

In some embodiments, as shown in Scheme 6, the methods include reacting a compound of formula (0) or a salt thereof with a compound of formula (E-3) or a salt thereof to form a compound of formula (B-3), a salt thereof, or a deuterated derivative of any which of the above The reaction of formula (A) and formula (8-3) can be carried out according to any convenient coupling reaction between alcohol and Ca.

Scheme 6.

KI oh 5

M 10 ОН H 7 (Ex. (83 v / 2

Nm t" M sev8rvo

M s Y y a at 10 o'clock in E-Z m i - vro () (-53) s -2-isvevv

KK 3 in (8-3)

In some embodiments, as shown in Scheme 7, the methods include reacting a compound of formula (2-1) with a compound of formula (X) to form a compound of formula (I), a salt thereof, or a deuterated derivative of any of the above. The reaction of formula (2-1) with the compound of formula (X) can be carried out in any convenient coupling reaction between nitrogen and halogen.

Scheme 7.

oh oh

M

(82), m? (Tues

N

M

B S, --

A ee M (Ka Oe 7 (2-1) e3 s in s) o oh

M

(c), m? (Tuesday St

OoShar in? with

Kk (B9 ()

In some embodiments, as shown in Scheme 8, the methods include reacting a compound of formula (2-1) with a compound of formula (X-1) to form a compound of formula (IM-C), a salt thereof, or a deuterated derivative of any of listed above. The interaction of the formula (2-1) with the compound of the formula (X-1) can be carried out in any convenient coupling reaction between nitrogen and halogen.

Scheme 8. о оо шк M ху

Mo. | N | (7 p Mn y M 2 x Oa M M -- t sh lyy (a su e3 s y M v / o (X-1) (SEU), o oo ke M hu no (ve

M - M 2 -pt v3 s w M (in kA /, th (Im-S) (SEP),

In some embodiments, as shown in Scheme 9, the methods include reacting a compound of formula (PE) or a salt thereof with a compound of formula (b) or a salt thereof to form a compound of formula (H), a salt thereof, or a deuterated derivative of any of the above . The interaction of formula (P) and formula (b) can be carried out in any convenient reaction between an amide and a sulfur atom, for example with bromine. In some embodiments, the reaction is carried out in the presence of a base, such as pyridine. The compound of the formula (H) or its salt can be oxidized to form the compound of the formula /()) or its salt. In some embodiments, the oxidizing agent is meta-chloroperoxybenzoic acid (pt-CPBA).

Scheme 9. (c) (c c) t

Mne 5 (s) a

Kk (ka (P) (o) v2 Z 1 ke is KO "

H --- oh? o is (ka (nH)

Her 1 v2 Z ' a V") t

N o e o is 4 in (ka (9)

In some embodiments, as shown in Scheme 10, the methods include reacting a compound of formula (7) with a compound of formula (II) to form a compound of formula (M), a salt thereof, or a deuterated derivative of any of the above. In some embodiments, the reaction is carried out in the presence of a base, such as sodium hydride.

Scheme 10.

o o o 27--M»z

НМ с в3 (ве) З '

N (th)

Ge ------- 4 (9) (in )d

She

(v2 p With 1 m ve) t

N

M in 3 s in 2-- 5M3 (td (M)

In some embodiments, as shown in Scheme 11, the methods include reacting a compound of formula (M) or a salt thereof with an amine to provide a compound of formula (M), a salt thereof, or a deuterated derivative of any of the above, wherein X is MH or M (C1-

Sdalkil). In some embodiments, the reaction of formula (M) and the amine can be carried out in the presence of M-chlorosuccinimide. A compound of formula (M) can be converted into a compound of formula (0), a salt thereof, or a deuterated derivative of any of the above. In some embodiments, the reaction is carried out under reducing conditions. In some embodiments, the reaction is carried out in the presence of palladium on carbon and hydrogen.

Scheme 11.

HER

(ve)a Z 1 and B) t

N

We are 3 in ----M3 (ta (M) o z (v2 Z 1 se a Io ) t

N

---vsh- in3-5Ж 2 in 2: - M3

AND

(in )d (M) o same (in2 Z 1 m in) t

N vu and 2: - M e

AND

(in )a (0)

In some embodiments, as shown in Scheme 12, the methods include reacting a compound of formula (0) or a salt thereof to form a compound of formula (P), a salt thereof, or a deuterated derivative of any of the above. In some embodiments, the reaction of formula (0) can be carried out in the presence of a base. In some embodiments, the base is triethylamine. In some embodiments, the reaction of Formula (0) can be carried out under heating.

Scheme 12.

o A (wag) 5 1 and c) t

N

Y tn o ut r 3 vi 2--1M»z 4 (vk )a (0) o (vy Z 1 ay vi) t

N su I Sh A-MN vi 7 (t)d (R)

Additional options include: 1. Compound of formula (1): o ka (v2 p Z 1 cha Kk ) t

N

Compound (I), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - Ring A is phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring ; - Ring B is a pyridinyl ring; - Ring Y is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - X is 0, MH or M (C1-C4 alkyl); - each CI! is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, З or 4; 5О0

- each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each IVF is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-- b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is 0, 1 , 2, 3, 4, 5 or 6; - each U is independently selected from C(K5)(b) groups, -O-- and -MVa- groups, where the heteroatom in -"X)K-87 is not bound with another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb are on the same carbon atoms together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl group,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

From C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 2. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where ring A is a phenyl ring, pyridyl ring or pyrazole ring, where ring A is optionally substituted with (K1)t.

C. The compound of embodiment 1 or 2, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K! independently selected from deuterium, C1-C2 alkyl groups and hydroxyl group and t is 0 or 1. 4. The compound according to any of embodiments 1--3, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where n is equal to 0. 5. The compound according to any of the embodiments 1-4, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring ХО is a 5-membered heteroaryl ring substituted with (К4)а4. 6. The compound according to any of the embodiments 1--4, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the Y ring is a phenyl ring, a pyridinyl ring, a pyrazolyl ring, an imidazolidinone ring, a pyrrolidinone ring or a pyridinone ring ring where Ring O is replaced by (K4)a4. 7. The compound according to any of the variants of implementation 1-4, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is c)

F x x

A 4 A (KO) (Ka (KO) (Ka

Yi Kh

A x ze - - (KO or Ka de r indicates the point of attachment of Ring O to Ring B. 8. The compound of embodiment 7, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is

M

4 and - where p indicates the point of attachment of Ring O to Ring B. 9. The compound according to any of embodiments 1-8, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from oxo groups or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 and where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 10. The compound according to any of embodiments 1-9, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 and where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group;

- each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 11. The compound according to any of embodiments 1-8, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 and where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 12. The compound according to any of embodiments 1-8, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from ro | with | z y z y U z 5 ion vo chu Frya o

EMS (c)

Zo U ; ,

AND

Yam What p du du i o s rr c. in ra c) about zhh, ra

Du" Du SU rya o is, tu ta ; where rez indicates the point of attachment of CA to ring 0. 13. The compound of any of embodiments 1-12, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein K is 3, 4, 5, or 6. 14. The compound according to any of embodiments 1-13, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where d is 1. 15. The compound according to any of embodiments 1-14, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (OGg, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- - and -MAr- groups, where the heteroatom in 27 is not bonded to another heteroatom in 2 and where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 16. The compound according to any of embodiments 1-14, its pharmaceutically acceptable salt or deuterated derivative of any of the listed above, where 7 is a bivalent linker of the formula (ОГг, where: - г is equal to 3, 4 or 5;

- each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, and: - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 17. The compound according to any of the embodiments 1-14, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (OGg, where: - g is 3, 4 or 5; - each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not bonded to another heteroatom in 2 and where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each Kb represents hydrogen. 18. The compound according to any of embodiments 1-14, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 represents a bivalent linker of the formula ()Hg, where: - r equals 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -O- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is hydrogen, and - each KB is independently selected from hydrogen and C1-C2 alkyl groups. 19. The compound according to any one of embodiments 1-18, a pharmaceutically acceptable salt or deutero thereof vana is a derivative of any of the above, where each short circuit independently represents

Co3. 20. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein the compound of Formula (I) is a compound

Formulas (II-A) or (1I-B): o Z / (c) Z 1 cha Kk ) t

N

M

3 s F 4 7 ve E (t 9 (I-A) or o Х y (ep Z 1 ay ve ) t

N

M- 7th century

WITH

(c) and (P-B), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring A is phenyl, 5-membered heteroaryl ring or b-membered heteroaryl ring - Ring B is a pyridinyl ring;

- Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, a hydroxyl group, an oxo group, a cyano group and - (YUK-K?7 groups, or optionally two KA together with the atoms to which they are attached, form a 5-- b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-02 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not connected connected to another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on one and the other the carbon atom itself together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyln their groups, halogens, hydroxyl group,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens;

Ko) - 4 is equal to 1, 2, Z or 4; - 7 is a bivalent linker of the formula (g, where: - g is 1, 2, 3, 4, 5 or 6; - each I. is independently selected from C(K8) (KU) groups, -0-- and -MAbB -- groups where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, C1-C2 haloalkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-02 haloalkyl groups; and - each CO is independently selected from hydrogen and C1-C2 alkyl groups. 21. The compound of embodiment 20, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (K1) v. 22. The compound of embodiment 20 or 21, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K ! is independently selected from deuterium, C1-C2 alkyl groups and a hydroxyl group, and t is 0 or 1. 23. A compound for any m of embodiments 20-22, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where n is 0. 24. The compound according to any of embodiments 20-23, its pharmaceutically acceptable salt or deuterated derivative of any which of the above, where Ring Y is a 5-membered heteroaryl ring substituted by (К4)а4. 25. The compound according to any one of embodiments 20-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring or a pyridinone ring, wherein Ring O is substituted with K4. 26. The compound of any of embodiments 20-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

(o, , i, m - 2 - -5 /

I'm J. J

A 4 4 (K)d (Ka (Ka (Ka

Yi Kh

A x ze y | 4 (Ka or Aa where p indicates the point of attachment of Ring O to Ring B. 27. The compound according to any of embodiments 20-23, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is

M

4 and - where p indicates the point of attachment of Ring O to Ring B. 28. The compound of any one of embodiments 20-27, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from oxo groups or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 29. The compound according to any of embodiments 20-28, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group;

- each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 30. The compound of any of embodiments 20-28, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(b) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 31. The compound of any of embodiments 20-28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from

Kk ro | with | z y z y U z

M EzS s vo

MA roya o

EzS (c)

In z z z ren i; rya o tu EzS o bo front "bo t vch ge vol

AND

Yam What p du du i o s yr

I ul ra o, o zhh, ra

Du»she SU r o o v i z de rez indicates the point of attachment of KA to ring 0. 32. The compound according to any of the embodiments 20-31, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where K is 3, 4, 5, or 6. 33. The compound of any of embodiments 20-32, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 34. The compound of any of embodiments 20-33, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5; - each Y is independently selected from C( K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups 35. The compound according to any of embodiments 20-33, its pharmaceutically acceptable salt or deuterated derivative any of the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5;

- each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 36. The compound according to any of the embodiments 20-33, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - g is 3, 4 or 5; - each I. is independently selected from C(K8)(K9) groups and -MAB- groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each Kb is hydrogen 37. The compound of any of embodiments 20-33, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 7 is a bivalent linker of the formula (g, where: - g is 3 . is hydrogen, and each Kb is independently selected from hydrogen and C1-C2 alkyl groups. 38. The compound according to any one of embodiments 20-37, its pharmaceutically acceptable salt or deutero vana is a derivative of any of the above, where each KZ is independently a POP3. 39. The compound according to embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of Formula I is a compound of Formula (SHPI-A) or (P-B): о оо (в2)е У 1

M m c ) t

N

M

M in si" 2 in Z (ka in (PI-A) or o oo (я2у У 1 ех ай в ) t

N

M

M-- I-» ozh7

AB in KI (ex: (PI-B), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring A is phenyl, 5-membered heteroaryl ring or b-membered heteroaryl ring - Ring B is a pyridinyl ring;

- Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each KIT is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which is necessarily and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3 , 4, 5 or 6; - each U is independently selected from С(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups rup, halogens, hydroxyl group,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens;

Ko) - 4 equals 1 or 2; - 7 is a bivalent linker of formula (I) g, where: - g is equal to 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 40. The compound of embodiment 39, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (K1)t. 41. The compound of embodiment 39 or 40, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K! independently selected from deuterium, C1-C2 alkyl groups, and hydroxyl group, and t is 0 or 1. 42. The compound of any one of embodiments 39-41, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein n is 0. 43. The compound of any of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring Y is a 5-membered heteroaryl ring substituted with (K4)a4. 44. The compound of any one of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring substituted with (K4)a. 45. The compound of any of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

(o, , i, m - 2 - -5 /

I'm J. J

A 4 4 (K)d (Ka (Ka (Ka

Yi Kh

A x ze y | 4 (Ka or Aa where p indicates the point of attachment of Ring O to Ring B. 46. The compound of any of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

M

4 and - where p indicates the point of attachment of Ring O to Ring B. 47. The compound of any one of embodiments 39-46, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from oxo groups or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 48. The compound according to any of embodiments 39-47, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group;

- each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 49. The compound of any of embodiments 39-47, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(b) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 50. The compound of any one of embodiments 39-47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from with | z y z y U z

M EzS s vo

MA roya o

EzS (c)

In z z z ren i; rya about that EzS about the front "because tu uch ge vol

AND

Yam What p du du i o s yr

I ul ra o, o zhh, ra

Du»she SU r o o v i z de rez indicates the point of attachment of KA to ring 0. 51. The compound according to any of the embodiments 39-50, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where K is 3, 4, 5 or 6. 52. The compound of any one of embodiments 39-51, a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above, wherein 4 is 1. 53. The compound of any one of embodiments 39-52, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5; - each Y is independently selected from C( K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups 54. The compound according to any of embodiments 39-52, its pharmaceutically acceptable salt or deuterated derivative any of the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5;

- each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 55. The compound according to any of the embodiments 39-52, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - g is 3, 4 or 5; - each I. is independently selected from C(K8)(K9) groups and -MAB- groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each Kb is hydrogen 56. The compound of any one of embodiments 39-52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 7 is a bivalent linker of the formula (g, where: - g is 3 . is hydrogen, and each Kb is independently selected from hydrogen and C1-C2 alkyl groups. 57. The compound according to any one of embodiments 39-56, its pharmaceutically acceptable salt or deutero vana is a derivative of any of the above, where each KZ is independently a POP3. 58. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein the compound of Formula I is a compound of Formula

IM-A: o oo (vu U o -ya- - M ra

M M in si" 7 4 Kk! a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above,

Where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X represents 0, MH or M (C1-C4 alkyl); - each KI is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, a cyano group and a hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups , halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo group, hydroxyl group, cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which is optional o and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where:

- K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or 5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of the formula (I r, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups 59. The compound of embodiment 58, a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above, wherein each R1 is independently selected from deuterium, C1-C2 alkyl groups and a hydroxyl group, and t is 0 or 1. 60. The compound of embodiment 58 or 59, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where n is 0. 61. The compound of any of embodiments 58-60, its a pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein Ring U is a 5-h len heteroaryl ring substituted by (К4)а4.

62. The compound of any of embodiments 58-60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring substituted with (K4)a. 63. The compound according to any of embodiments 58-60, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is (o, x A, c: i, p M c 2 -/

Ж Ж Ж -e zv (Vya (4 (B) (Va

Y Z so u u ; ; (B) or Aa where p indicates the point of attachment of Ring O to Ring B. 64. The compound of any of embodiments 58-60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

M in where p indicates the point of attachment of Ring O to Ring B. 65. The compound of any one of embodiments 58-64, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 66. The compound according to any of embodiments 58-65, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(b) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 67. The compound of any of embodiments 58-66, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -O-(U)K-K7 groups, wherein: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 68. The compound of any of embodiments 58-67, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from

Let me lie in the twisted wind

Until then, I will rub them in the left veto

KK reve rani p Ushisochi du dya ho, oh se ram things

ROD" To r o v) tu

And , where p indicates the point of attachment of CA to ring 0. 69. The compound of any of embodiments 58-68, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where K is 3, 4, 5, or 6. 70. The compound of any of embodiments 58-69, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 71. The compound of any of embodiments 58-70, its a pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (g, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, - 0- and -MAbB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each Kb is independently selected from hydrogen and C1-C2 alkyl groups 72. The compound of any of embodiments 58-70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the following above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5; - each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 73. The compound according to any of embodiments 58-70, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - g is 3, 4 or 5; - each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where:

Zo - each K8 and KU independently selected from hydrogen and deuterium; and - each Kb is hydrogen. 74. The compound according to any of the embodiments 58-70, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is hydrogen; and - each CO is independently selected from hydrogen and C1-C2 alkyl groups. 75. The compound of any one of embodiments 58-74, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each CO is independently a POP3. 76 The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the compound of Formula I is a compound of Formula

IM-V:

о оо (в2)в У о --я - М В

M M

VZ Sh ikh

There is; 89 и (td Кк (свв в (М.В), its pharmaceutically acceptable salt or deuterated derivative of any of the above), where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y represents is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each CI! is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1 - C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, cyano groups and - (YUK-K7 groups, or optionally two K4 together with the atoms to which they are attached form 5 - b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where : - K equals 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-Б87 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 77. The compound of embodiment 76, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K8 and CO is independently selected from hydrogen, deuterium, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups. 78. The compound of embodiment 76 or 77, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K8 and KU is H.

79. The compound of any one of embodiments 76-78, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K1 is independently selected from deuterium, C1-C2 alkyl groups, and hydroxyl group, and t is 0 or 1. 80. A compound according to any of embodiments 76-79, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0. 81. A compound according to any of embodiments 76-80, a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above, wherein Ring Y is a 5-membered heteroaryl ring substituted with (K4)a4. 82. The compound of any of embodiments 76-80, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring substituted with (K4)a. 83. The compound according to any of embodiments 76-80, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is (o, x, x, M 2 2 y /

I am I

A 4 4 (K)d (Ka (KO (Ka

Y X g | 4 (Ka or (K)d ), where p indicates the point of attachment of Ring O to Ring B. 84. The compound according to any of embodiments 76-80, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is a

M

4 (in - where re indicates the point of attachment of Ring O to Ring B. 85. The compound of any of embodiments 76-84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from oxo groups or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(K5)(Kb) groups, -О-- and -MVa- groups, where the heteroatom in -"X)K-87 is not connected to another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group ,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

Zo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and

- K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 86. The compound according to any of embodiments 76-44, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 87. The compound of any of embodiments 76-84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -O-(U)K-K7 groups, wherein: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(b) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or H5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is not necessarily independently substituted by one or more groups,

With selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl group,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 88. The compound of any of embodiments 76-44, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 independently represents

Dolya SR et ; ; , I Y

EzZS EzS with Fr. | from Kolya

M vs MA si 5.

"lotu r ia ote otu pri vbfrtnchu ih v chu" va Tu v vya

That's it

Who is it?

I am from the same; | To whom o, rr ra o o, o rya

Drsya , tu rya o is, tu and , where rez indicates the point of attachment of KA to ring 0. 89. The compound according to any of embodiments 76-88, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where K is 3, 4, 5 or 6. 90. The compound of any one of embodiments 76-89, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 91. The compound of any one from embodiments 76-90, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is independently selected from hydrogen and deuterium; and - each Kb is independently selected from hydrogen and C1-C2 alkyl groups. 92. The compound according to any of the variants of implementation 76-90, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is independently selected from hydrogen and deuterium; and - each Kb is independently selected from hydrogen and methyl. 93. The compound of any of embodiments 76-90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein:

- r equals 3, 4 or 5; - each K8 and KU is independently selected from hydrogen and deuterium; and - each Kb is hydrogen. 94. The compound according to any of the variants of implementation 76-90, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is hydrogen; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 95. The compound according to any of the embodiments 76-94, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each KZ is independently a POP3. 96. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the compound of Formula | is a compound

IM-S formulas: o o o (v2)a MU o --8x

M. and Mich

H M M k-/ in

Kk (B) -3- ex r

C 809 b c (SK), K (IM-C), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - each CI independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ represents is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, halogen alkyl groups, hydroxyl group, C1-C2 alkoxyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2;

- r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 97. The compound of embodiment 96, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K8 and CO is independently selected from hydrogen, deuterium, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups. 98. The compound of embodiment 96 or 97, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K8 and KU is H. 99. The compound of any of embodiments 96-98, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, wherein each R1 is independently selected from deuterium, C1-C2 alkyl groups, and hydroxyl group, and t is 0 or 1. 100. The compound of any one of embodiments 96-99, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein n is 0. 101. The compound of any one of embodiments 96-100, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein each K4 independently selected from the oxo group or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups,

Z is optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 102. The compound according to any of embodiments 96-100, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 103. The compound of any of embodiments 96-100, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from the oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and bo - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and

- K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 104. The compound of any of embodiments 96-100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from

EzZS EzZS ro | and | and rya with

EzS EzS with Fr. | from Kolya

M iony vo rchch with o

Ezs F. ra ro in

In z z z roya o rya c) tu EzS o o o ro

EzS in EzS o o M ro M i gzs EzS o EzS in ura roya Ou y

EzS in ke; o nie o j lo

And At

J

A o, s pom vo; | To whom J, rom re and pria | i rya o o v ta ; where p indicates the point of attachment of CA to ring 0. 105. The compound of any one of embodiments 96-104, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein K is 3, 4, 5, or 6. 106. The compound of any one of embodiments 96-105, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 107. The compound of any one of embodiments 96-106, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is independently selected from hydrogen and deuterium; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 108. The compound according to any of the variants of implementation 96-106, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 109. The compound according to any of the variants of implementation 96-106, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is independently selected from hydrogen and deuterium; and - each Kb is hydrogen. 110. The compound according to any of the variants of implementation 96-106, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; - each K8 and KU is hydrogen; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 111. The compound of any one of embodiments 96-110, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each KZ is independently a POP3. 112. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein the compound of Formula I is a compound of Formula

MA:

o o o (woo In what - M

M M

" 3 and 4 C is a pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(K5)(Eb) groups, -O-- and -MVa- groups, where the heteroatom in -(X)K-87 is not bonded to another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl group,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of the formula (r, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups 113. The compound of embodiment 112, a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above, wherein each K1 is independently selected from deuterium, C1-C2 alkyl groups, and a hydroxyl group, and t represents 0 or 1. 114. The compound of embodiment 112 or 113, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein n is 0.

115. The compound of any one of embodiments 112-114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring Y is a 5-membered heteroaryl ring substituted with (K4)a4. 116. The compound according to any of embodiments 112-114, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is a pyrazolyl ring substituted with (K4)a. 117. The compound according to any of embodiments 112-114, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is (o, z x, M 2 2 u /

I am I

A 4 4 (K)d (Ka (KO (Ka

Yi Kh

4 | 4 (KO or (Ka), where p indicates the point of attachment of Ring O to Ring B. 118. The compound according to any of embodiments 112-117, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is

M

4 where re indicates the point of attachment of Ring O to Ring B. 119. The compound of any one of embodiments 112-118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups,

Z is optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 120. The compound of any of embodiments 112-118, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -(U)K-K7 groups, where:

- K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 121. The compound of any one of embodiments 112-118, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from the oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens.

122. The compound of any one of embodiments 112-118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from

EzZS EzS rya z vo rn

In, 5 of you ra se in:

More about

EzS Fr

In the middle of these, I will throw them into the river

Yam What p du du i o s yr

I ul ra o, o zhh, ra

Du»she SU rya o is, tu and ; where rez indicates the point of attachment of CA to ring 0. 123. The compound of any one of embodiments 112-122, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein K is 3, 4, 5, or 6. 124. The compound of any one of embodiments 112-123, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 125. The compound of any one of embodiments 112-124, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 126 A compound of any one of embodiments 112-124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any from the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5;

- each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 127. The compound according to any of embodiments 112-124, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - g is 3, 4 or 5; - each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each Kb is hydrogen 128. The compound of any one of embodiments 112-124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 7 is a bivalent linker of the formula (g, where: - g is 3 . is hydrogen; and - each Kb is independently selected from hydrogen and C1-C2 alkyl groups. 129. The compound according to any one of embodiments 112-128, its pharmaceutically acceptable salt ab o deuterated derivative of any of the above, where each KZ is independently a POP3. 130. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein the compound of Formula I is a compound of Formula

U-V: o o o (Wu U

Shy what; - Mod

M

M vch (t) v3 (SReRU), (U-V), its pharmaceutically acceptable salt or deuterated derivative of any of the above,

Where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each CI! is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2 . 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form 5- b-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more gr groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6;

- each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r equals 3, 4 or 5; and - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups. 131. The compound of embodiment 130, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K8 and KU is independently selected from hydrogen, deuterium, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups. 132. The compound of embodiment 130 or 131, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K8 and KU is H. 133. The compound of any of embodiments 130-132, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, wherein each R1 is independently selected from deuterium, C1-C2 alkyl groups, and hydroxyl group, and t is 0 or 1. 134. The compound of any one of embodiments 130-133, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein n is 0. 135. The compound of any one of embodiments 130-134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring U is a 5-membered

Zo is a heteroaryl ring substituted by (K4)4. 136. The compound according to any one of embodiments 130-134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring substituted with (K4)a. 137. The compound according to any of embodiments 130-134, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is );

Sh i, s: i, l M s 2 -/

Zh x x -e (Ba (Ka (Ka (B7)d

Y Z o u u ; ; (B) or Aa where p indicates the point of attachment of Ring O to Ring B. 138. The compound of any one of embodiments 130-137, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

M in where p indicates the point of attachment of Ring O to Ring B. 139. The compound of any one of embodiments 130-138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 140. The compound according to any of embodiments 130-138, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 141. The compound of any of embodiments 130-138, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from the oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 142. The compound of any one of embodiments 130-138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from

Let me lie in the twisted wind

Until then, I will rub them in the left veto

KK reve rani p Ushisochi du dya ho, oh se ram things

DR ODU To

Du»she SU r o o v ta ; where p indicates the point of attachment of CA to ring 0. 143. The compound of any one of embodiments 130-142, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein K is 3, 4, 5, or 6. 144. The compound of any one of embodiments 130-143, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 145. The compound of any one of embodiments 130-144, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; and - each K8 and KU is independently selected from hydrogen and deuterium. 146. The compound according to any of the variants of implementation 130-144, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; and - each K8 and KU is hydrogen. 147. The compound according to any of the embodiments 130-144, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; and - each K8 and KU is a deuterium. 148. The compound according to any of the variants of implementation 130-144, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - d is equal to C or 4; and - each K8 and KU is hydrogen. 149. The compound of any one of embodiments 130-148, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each KZ is independently a POP3. 150. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein the compound of Formula I is a compound of Formula

MI-A or MI-B: o o o (well U 1 (v'z c XX

M in si" 2 in Z zo (vd in (MI-A) or o oo (2 U oz and Z o ---x db. A

M, M

J

4 3 (in and in (MI-B), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring, or b-membered heteroaryl ring - each C1 independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1- C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo group, hydroxyl group, cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached, form a 5-b-member nni cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

From C1-C2 alkoxy groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of formula (I) g, where: - g is equal to 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 151. The compound of embodiment 150, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each R1 is independently selected from deuterium, C1-C2 alkyl groups, and hydroxyl group, and t is 0 or 1. 152. The compound of in embodiment 150 or 151, a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above, wherein n is 0.

153. The compound of any one of embodiments 150-152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring Y is a 5-membered heteroaryl ring substituted with (K4)a4. 154. The compound of any of embodiments 150-152, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring substituted with (K4)a. 155. The compound according to any of embodiments 150-152, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where Ring O is (o, x, l, M - 2 - ryn x x x

A 4 4 (K)d (Ka (KO (Ka

Yi Kh

4 | 4 (Kk )a or (Kk Ia ,; where p indicates the point of attachment of Ring O to Ring B. 156. The compound according to any of embodiments 150-152, its pharmaceutically acceptable salt or deuterated derivative of any of the above , where Ring O is

M

4 where re indicates the point of attachment of Ring O to Ring B. 157. The compound of any one of embodiments 150-156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups,

Z is optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 158. The compound of any one of embodiments 150-156, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -(U)K-K7 groups, where:

- K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 159. The compound of any of embodiments 150-156, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -O-(U)K-K7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens.

160. The compound of any one of embodiments 150-156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from

EZS EzZS rya z vo rn

In, 5 of you ra se in:

More about

EzS Fr

In the middle of these, I will throw them into the river

Yam What p du du i o s rr c. uh ra o, o zhh, ra

Du»she SU rya o is, tu and ; where rez indicates the point of attachment of CA to ring 0. 161. The compound of any one of embodiments 150-160, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein K is 3, 4, 5, or 6. 162. The compound of any one of embodiments 150-161, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 163. The compound of any one of embodiments 150-162, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 164 A compound of any one of embodiments 150-162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any from the above, where 7 is a bivalent linker of the formula (MG, where: - r is 3, 4 or 5;

- each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each CO is independently selected from hydrogen and methyl. 165. The compound according to any of the variants of implementation 150--162, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a bivalent linker of the formula (MG, where: - g is 3, 4 or 5; - each I. is independently selected from C(K8)(KU) groups and -MAB- groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen and deuterium, and - each Kb is hydrogen. 166. The compound of any one of embodiments 150-162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 7 is a bivalent linker of the formula (g, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9) groups, -O- and -MAbB- groups, where the heteroatom in 2 is not bonded to another heteroatom in 2, where: - each K8 and KU is hydrogen, and - each KB is independently selected from hydrogen and C1-C2 alkyl groups. 167. The compound according to any one of embodiments 150-166, a pharmaceutically acceptable salt thereof and for the deuterated derivative of any of the above, where each KZ is independently a POP3. 168. The compound of embodiment 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, wherein the compound of Formula I is a compound of Formula

MI-S or MI-0: о оо (в2у У - 1 у/р!1 (В 4 ХХ

M in si, /, (vy) v3 vro h (SKK), (MI-S) or o oo (vu U - 1 /r!1 (Kt 4 4

M

829 (pa vi (steve), (MI-5), its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y represents is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X is 0, MH or M (C1-C4 alkyl);

- every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-b-membered cycloalkyl or heterocyclyl ring, which optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl group,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r is equal to C or 4; and

Zo - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkoxy groups and C1-C2 haloalkyl groups. 169. The compound of embodiment 168, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K8 and KU is independently selected from hydrogen, deuterium, halogens, C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups. 170. The compound of embodiment 169 or 169, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K8 and KU is H. 171. The compound of any of embodiments 168-170, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, wherein each R1 is independently selected from deuterium, C1-C2 alkyl groups, and hydroxyl group, and t is 0 or 1. 172. The compound of any one of embodiments 168-171, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, where n is 0. 173. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, where Ring OO 5-membered heteroaryl ring substituted by (K2)a. 174. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is a pyrazolyl ring substituted with (K4)a. 175. The compound of any of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

(o, , i, m - 2 rya - -|-- x x x shchi 4 (K7)d (Ka (K)4 (Ka

Y X and | 4 (KO or Ka where p indicates the point of attachment of Ring O to Ring B. 176. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring O is

M

4 and - where p indicates the point of attachment of Ring O to Ring B. 177. The compound of any of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from oxo groups or -(U)K-K7 groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 178. The compound according to any of embodiments 168-176, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or -(U)K-K7 groups, where: - K equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group;

- each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 179. The compound of any one of embodiments 168-176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from an oxo group or -O-(U)K-K?7 groups, where: - K is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group,

C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens. 180. The compound of any one of embodiments 168-176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each K4 is independently selected from with | z y z y U z

M EzS s vo

MA roya o

EzS (c)

In z z z ren i; rya about that EzS about the front "because tu uch ge vol

AND

Yam What p du du i o s rr c. in ra o, o zhh, ra

Du»she SU rya o is, tu and ; where rez indicates the point of attachment of CA to ring 0. 181. The compound of any one of embodiments 168-180, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein K is 3, 4, 5, or 6. 182. The compound of any one of embodiments 168-181, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein 4 is 1. 183. The compound of any one of embodiments 168-182, its pharmaceutically acceptable a salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; and - each K8 and KU is independently selected from hydrogen and deuterium. 184. The compound according to any of embodiments 168-182, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; and - each K8 and KU is hydrogen. 185. The compound according to any of the embodiments 168-182, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is 3, 4 or 5; and - each K8 and KU is a deuterium.

186. The compound according to any of the variants of implementation of 168-182, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - d is equal to C or 4; and - each K8 and KU is hydrogen. 187. The compound of any one of embodiments 168-186, wherein each KZ is independently a POP3. 188. The compound of any one of embodiments 20-57, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the designated carbon of formula (PI-A) or (PI-A) has 5-stereochemistry, and where the marked " carbon of formula (1I-B) or (PI-B) has K- stereochemistry. 189. The compound according to any of the embodiments 58-187, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the carbon of any of the formulas (IM-A), (IM-B), ( IM-O), (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-Y) have 5-stereochemistry. 190. A compound of any -which of the variants of implementation of 58-187, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the carbon of any of the formulas (IM-A), (IM-B), (IM-C) is indicated, (M-A), (M-B), (MI-A), (MI-B), (MI-C) and (MI-Y) have E-stereochemistry. 191. A compound selected from MoMo compounds. 1-302 shown in Figure 1, its pharmaceutically acceptable salts and deuterated derivatives of any of the above. 192. A compound selected from MoMo compounds 303-309 shown in Figure 1, its pharmaceutically acceptable salts and deuterated derivatives of any of the above. 193. Compound selected from: о оо

Hm shk M dra

M | and r - MAK

M M M or yo sn sn, Z not o oo

M

)

In M

M | - y Mach -e -sh- ns MN sn,

oh oh

J and M Uh ho | A Y 5-4 M t (c) 4 - no C mn sn, o oo

Ж воша 2 2 t M shli ie y: ш-Ш2Я not МН not о оо

And your r M o o -- M m ate: - not MN sleep, o o o

Ж рай M Ух хх | y I 5-47) M M z y --- ns M

And "en,

E sn,

oh oh

We

WITH

S r KD

E M-M M M x / M

Oh no

E sn, o oo

M

E 5 ak M y i | AND

E Mu - Mom, - not MN not (in) o o / y:

M M- o | y: N MN y ne M M M no no no z no SN, o oo

WE

Z ak M hu

AI

M 2-8 and (c) -- not and not its pharmaceutically acceptable salts or deuterated derivatives of any of the above. 194. A pharmaceutical composition comprising at least one compound selected from the compounds of any one of embodiments 1-191, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above and optionally one or more of: (a) II compounds:

M

(c) in x on

So about E M -7 on ,

a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above; (B) PI compounds: he (c) (c)

M

N

M

H its pharmaceutically acceptable salt or deuterated derivative of any of the above; and (c) a pharmaceutically acceptable carrier. 195. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to any of the variants of implementation 1-191 or a pharmaceutical composition according to the variant of implementation 194. 196. The use of at least one compound selected from the compounds according to any of the variants embodiment 1-191, a pharmaceutically acceptable salt or deuterated derivative thereof of any of the above and optionally one or more of: (a) Compound II:

M

(in)

E x v (v) o E M -7

OH, its pharmaceutically acceptable salt or deuterated derivative of any of the above; (B) PI compounds: he (c) (c)

M

N

M

H its pharmaceutically acceptable salt or deuterated derivative of any of the above; for the treatment of cystic fibrosis. 197. Compound of Formula (X):

o Kf (ve2)p Z 1 y Kk ) t

To us

Kk c in (9), its salt or deuterated derivative of any of the above, where: - Oa is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - X represents 0, MH or M (C1-C4 alkyl); - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - 7 is a bivalent linker of the formula (g), where: - g is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups , where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Kb is independently selected from hydrogen and C1-C2 alkyl groups. 198. Compound of Formula (U): o Kf (v2 p Z 1 cha E ) t

What? (in is) (td not Same in (o its salt or deuterated derivative of any of the above), where:

Zo - OB is a halogen; - K10 is hydrogen or a protective group; - Ring A is a phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - Ring B is a pyridinyl ring;

- Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X represents 0, MH or M (C1-C4 alkyl); - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-- b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is 0, 1 , 2, 3, 4, 5 or 6; - each U is independently selected from C(K5)(Kb) groups, -0-- and -MVa- groups, where the heteroatom in -(U)K-

K?7 is not bonded to another heteroatom in -(M)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2

From haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 199. The method of obtaining the compound of formula (I)

But oh well

Kk c (t a c (in its pharmaceutically acceptable salt or deuterated derivative of any of the above), which contain a combination of the MH group of the C ring and the OB group of the B ring of the compound of the formula (U-1):

o Kf e2 Z 1 (va m V) t

What?

Кк с (г) во (Х-), its salt or deuterated derivative of any of the above, where: - ОБ is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X represents 0, MH or M (C1-C4 alkyl); - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-- b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is 0, 1 , 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bound with another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb are on the same carbon atoms together form a C3-5 cycloalkyl group or oxo;

Zo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Kb is independently selected from hydrogen and C1-C2 alkyl groups; to form a compound of formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above.

200. The method of embodiment 198, wherein said coupling is performed in the presence of a base. 201. The method of obtaining the compound of the formula (U)

N

Ge u

Same as in (ba (9), its salt or deuterated derivative of any of the above, where the interaction of the compound of formula (A), its salt or deuterated derivative of any of the above with the compound of formula (B), its salt or deuterated a derivative of any of the above with the formation of the indicated compound of formula (U), its salt or a deuterated derivative of any of the above:

M

(A) and (B) (ka 3

Ge

In v2 Z ' "7 v") t

What? (c) volume 7 "Zh

M

4 3 ( 10 (vd g) optional removal of protection from the M-protecting group of ring C of formula (U), where -O6 is a halogen;

K10 of the formula (U) represents hydrogen or an M-protecting group;

K10 of formula (B) is an M-protecting group, and ring A, ring B, ring 0, X, K1, t, K2, M, KZ, KA, СО, 7, K10 and their variables are as indicated in the variant implementation 1. 202. The method according to the variant of implementation 201, in which the interaction of the compound of Formula (A), its salt or deuterated derivative of any of the above with the compound of formula (B), its salt or deuterated derivative of any of the above is indicated , is performed in the presence of a base. 203. The method according to embodiment 201, in which the interaction of the compound of formula (A), its salt or deuterated derivative of any of the above with the compound of formula (B), its salt or deuterated derivative of any of the above includes the interaction of the compound of formula (A), its salt or deuterated derivative of any of the above with a coupling reagent and subsequently with a compound of formula (B), its salt or deuterated derivative of any of the above, in the presence of a base.

204. The method of obtaining the compound of the formula (U-2): o zhi 2 5 povo

What? 10

OV; y "Z soda (k)d in IS I (y-d), its salt or deuterated derivative of any of the above, where: - OB is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X represents 0, MH or M (C1-C4 alkyl); - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-- b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is 0, 1 , 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bound with another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb are on the same carbon atom

Zo together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; - r equals 1, 2, 3, 4 or 5; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - K10 is hydrogen or a protective group; which includes the interaction of a compound of the formula (A), its salt or a deuterated derivative of any of the above with a compound of the formula (B-2), its salt or a deuterated derivative of any of the above to form the specified compound of the formula (U-2) , its salt or deuterated derivative of any of the above:

o x (in) M nm in t (in st. on o? - MN o I io /

Mo urine (ka (A) dz

Ge (v-2) o Kf v2 Z 1 (va "7 V) t

N ha 10 v") Shk: МН "Ж se (v7) v ISv'k IN (y-2) a . 205. The method according to variant implementation 204, in which the interaction of the compound of Formula (A), its salt or deuterated derivative is specified of any of the above with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the above is performed in the presence of a base. 206. The method according to embodiment 205, wherein the interaction of the compound of formula (A), its of a salt or deuterated derivative of any of the above with a compound of formula (B-2), a salt thereof or a deuterated derivative of any of the above includes the interaction of a compound of formula (A), a salt thereof or a deuterated derivative of any of the above with coupling reagent and subsequently with the compound of the formula (B-2), its salt or deuterated derivative of any of the above, in the presence of a base. 207. The method according to any of items 204-206, which additionally contains the interaction of the compound of the formula (0 ), its salt or deuterated derivative of any of the above with sp compound of the formula (E-2), its salt or deuterated derivative of any of the above with the formation of the indicated compound of the formula (B-2), its salt or deuterated derivative of any of the above: o xx

In oh MN» nt c) t and c) In: 8re

NhM t M s ISEK) M U

MN

3 ko E-2 (9) yaz ve

M s ISVZEYag 3 e3 (in-2) where Ka is a halogen. 208. The method of obtaining the compound of the formula (U-3):

She

2 Z ' 7 V) t

What? 10

OHM; 5 "Ж and (c) in IS I h (U-3), its salt or deuterated derivative of any of the above, where the interaction of the compound of formula (A), its salt or deuterated derivative of any of the above with the compound of the formula (B-3), its salt or a deuterated derivative of any of the above with the formation of the specified compound of the formula (B-3), its salt or a deuterated derivative of any of the above: o x o M

Nv v t (v ma y o? nya Ge) se I io / z

MS ISVZVYAg

AND

(ka (A) v

Ge (8-3)

I M v2 Z 1 (in 7 in t

N ha

OHM; o "Ж y (v7) in ISv'k IN (v-3) a . 209. The method according to embodiment 208, in which the interaction of a compound of Formula (A), its salt or a deuterated derivative of any of the above with a compound of the formula (B-3), its salt or a deuterated derivative of any of the above is specified performed in the presence of a base. 210. The method according to embodiment 208, which is characterized in that the specified interaction of the compound of formula (A), its salt or deuterated derivative of any of the above with the compound of formula (B-3), its salt or deuterated derivative of any of of the above includes the interaction of a compound of the formula (A), its salt or a deuterated derivative of any of the above with a coupling reagent and subsequently with a compound of the formula (B-3), its salt or a deuterated derivative of any of the above, in the presence of a base. 211. The method according to any of paragraphs 208-210, which additionally contains the interaction of a compound of the formula (0), its salt or a deuterated derivative of any of the above with a compound of the formula (E-3), its salt or a deuterated derivative of any of the above with the formation of the indicated compound of the formula (B-3), its salt or deuterated derivative of any of the above:

about h

M ohon sht c) t

What?

From c) y

Nom and Darty - (c)

Ge; ve E-Z / (0) in v

M s IS ve

Ge; (B-3) 212. The method of obtaining the compound of the formula (I) o Kf (c) Z 1 m Kk t

N

M

9 Efe

WITH

(and and () its pharmaceutically acceptable salt or deuterated derivative of any of the listed moles. (a, (B) above, where ring Y is 9 , containing the interaction of the compound of formula (X), its salt or deuterated derivative of any any of the above with the compound of formula (2-1), its salt or deuterated derivative of any of the above:

o Kf (v2 n C 1

M. m VU) t 42 --/ (24) (KO og M 7 vAOsh v o Kf (v2 Z 1

M i ) t

N

M

-

I am M; -- 3 pi) and BA e3 (I) where: - Oa is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X represents 0, MH or M (C1-C4 alkyl); - every CI! independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (UK-K7 groups, or optionally two K4 together with the atoms to which they are attached form a 5-- b-membered cycloalkyl or heterocyclyl a ring which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is 0, 1 , 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bound with another heteroatom in -(U)K-K7, where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb are on the same carbon atoms together form a C3-5 cycloalkyl group or oxo;

Zo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and

- each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9) groups, -0- and -MAbB- groups, where the heteroatom in 2 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 haloalkyl groups,

C1-C2 alkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 213. The method of obtaining a compound of the formula (IM-C): о оо (в2)а MU

M m va

H 1 (Tue

M - Mykh ah M k-/ Z y 4 Kk s (KOd o sh- ekh M, / in 8ro b (sk), Kk (IM-C), its pharmaceutically acceptable salt or deuterated derivative of any of the above, containing the interaction of a compound of the formula (X-1), its salt or a deuterated derivative of any of the above with a compound of the formula (2-1), its salt or a deuterated derivative of any of the above:

OO oo (Va M u M Zh

Dekn | and | (Vt z» x -i M. ikh 4 removed, (2-1) og M M (Ba v3

СХ m (х-1) в3 / ТУдБ (СтеРУ), о оо (в2) M

Zh M Zh

1 9 r»

WITH

4 Kk (V)dmya with u. Mo (ms) 3 ra te (STRU), where:

- Oa is a halogen; - the carbon marked "7" has 5-stereochemistry or K-stereochemistry; - Ring Y is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each CI is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and - (OK-K?7 groups, or optionally two Kiraz with the atoms to which they are attached, forming 5- b -membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups , selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб) groups, -О-- and -МВа- groups, where the heteroatom in -"Х)К-87 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5 cycloalkyl group or oxo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl groups,

C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C2 alkyl groups; and - K7/ selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups,

Z is optionally substituted by one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2 alkyl groups, hydroxyl group, C1-C2 alkyl groups and C1-C2 haloalkyl groups; and - each KO is independently selected from hydrogen and C1-C2 alkyl groups. 214. The compound of any of embodiments 1-190, wherein the compound is in the form of a pharmaceutically acceptable salt. 215. The compound of embodiment 214, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 216. The compound of embodiment 215, wherein the pharmaceutically acceptable salt is a calcium salt. 217. The compound of any of embodiment 191, wherein the compound is in the form of a pharmaceutically acceptable salt. 218. The compound of embodiment 217, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 219. The compound of embodiment 218, wherein the pharmaceutically acceptable salt is a calcium salt. 220. The compound of any one of embodiment 192, wherein the compound is in the form of a pharmaceutically acceptable salt. 221. The compound of embodiment 220, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 222. The compound of embodiment 221, wherein the pharmaceutically acceptable salt is a calcium salt. 223. The compound of any of embodiment 193, wherein the compound is in the form of a pharmaceutically acceptable salt. 224. The compound of embodiment 223, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 225. The compound of embodiment 224, wherein the pharmaceutically acceptable salt is a calcium salt.

226. The compound according to embodiment 193, in which the compound is o o o

M o | ex 7th

N r - MAX

M M M or pd! yo sn sn, C ne 221. The compound according to any of the embodiments 193, in which the compound is in the form of a calcium salt: o o o

AND

--k M to

M | and r - MAX

M M M chi yo sn sn, 3 pao . 228. The compound according to embodiment 193, in which the compound is o o o

M/Y

Z hu M y

M | and A Mach - and MM M d- not МН сн, 229. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: o o o

M/Y

WITH

-k M dDh

M | ря А Ma - and М M -- not МН сн, ' 230. The compound according to the embodiment 193, in which the compound is о оо

M/Y

From and 7 xx

KU | and her ear

M d-O ns C mn sn, 231. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: o o o

M

With and and Uh that | And Y

Mu d8- -t3O- ne ( mn sn, 232. The compound according to embodiment 193, in which the compound is о оо

M

Uh ay and zn M | to and MAX and o- M M M -- ns МН ne 233. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: o o o

M

5 x M and 2 2 M | ря и Ма и 0-7 М M - No МН no 234. The compound according to embodiment 193, in which the compound is о оо

M/Y

WITH

-k M dDh

M | ря А Ma - о) о -І М M -- ne МН сн, 235. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: о оо

M

WITH

In M r

M | y-- y Myu - c) not ФА ММ д- not МН сн, 236. The compound according to the embodiment 193, in which the compound is о оо

M

5 and M Uh what | and Yi rya

M pi y -- not M.

E CH,

E sn, 237. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: o o o

M

5 and 7 Uh what | and Y

Mr. M. and Mr. M.

E sn,

E sn, 238. The compound according to embodiment 193, in which the compound is

Where are we?

N ro /

E M-m M M Gd / M

Oh, and Us

E sn, 239. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: o o

Are we in m?

N ro /

E M-Mm M M Gd / M

Oh, and Us

E dream 240. The compound according to embodiment 193, in which the compound is o o o

E M

Ex 7 and | AND

E Mu - Ma and M M - not MH not 241. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: o o o

E M oh 7 y y | AND

E Mu and Ma and M M - not МН not 242. The compound according to embodiment 193, in which the compound is (c) o 9 / and:

M M-- about | y: N MN r no M M M no no no

With no CH,

243. The compound according to any of the variants of implementation 193, in which the compound is in the form of a calcium salt: (c) o 9 / and:

M M-- about | Тх Н МН - not ММ М not not not with not CH, 244. The compound according to embodiment 193, in which the compound is о оо

WE

WITH

In M -k

AI

MU r r (c) -- no and no 5 . 245. The compound according to any one of embodiments 193, in which the compound is in the form of a calcium salt: o o o

WE

WITH

In M -k

AI

MU - - (c) d- no Ky no 246. The method of treating cystic fibrosis according to embodiment 195, in which the compound is in the form of a pharmaceutically acceptable salt. 247. The method of embodiment 246, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 248. The method of embodiment 247, wherein the pharmaceutically acceptable salt is a calcium salt. 249. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to embodiment 192. 250. A method of treating cystic fibrosis, which includes administering to a patient in need of it, a compound of any of embodiments 193 or 226-245. 251. The compound of any of embodiments 249 or 250, wherein the compound is in the form of a pharmaceutically acceptable salt. 252. The method of embodiment 251, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 253. The method of embodiment 252, wherein the pharmaceutically acceptable salt is a calcium salt. 254. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to any one of options 1-190, in which the compound is administered in combination with Compound PS or a pharmaceutically acceptable salt or deuterated derivative thereof.

255. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to embodiment 191 of the invention, in which the compound is administered in combination with

Compound I or its pharmaceutically acceptable salt or deuterated derivative. 256. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to embodiment 192 of the invention, in which the compound is administered in combination with

Compound I or its pharmaceutically acceptable salt or deuterated derivative. 257. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound according to any of embodiments 193 or 226-245, wherein the compound is administered in combination with

Compound I or its pharmaceutically acceptable salt or deuterated derivative. 258. The method according to any of embodiments 254-257, in which the deuterated derivative

Compound I is Compound PI. 259. The method of treating cystic fibrosis, which includes administering to a patient who needs it, a compound according to any of paragraphs 1-190, in which the compound is administered in combination with (a) compound YII and (B) compound PI or its deuterated derivative. 260. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to embodiment 191 of the invention, in which the compound is administered in combination with (a) compound II and (B) compound II or its deuterated derivative. 261. A method of treating cystic fibrosis, which includes administering to a patient in need of it a compound according to embodiment 192 of the invention, in which the compound is administered in combination with (a) compound HER and (B) compound PI or a deuterated derivative thereof. 262. The method of treating cystic fibrosis, which includes administering to a patient who needs it, a compound according to any of paragraphs 193 or 226-245, in which the compound is administered in combination with (a) compound II and (B) compound II or its deuterated derivative. 263. The method according to any of embodiments 259-262, in which the deuterated derivative

Compound I is Compound PI. 264. The method of any of embodiments 254-262, wherein the compound is in the form of a pharmaceutically acceptable salt. 265. The method of embodiment 264, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

Zo 266. The method according to embodiment 265, in which the pharmaceutically acceptable salt is a calcium salt. 267. A pharmaceutical composition comprising a compound of embodiment 191 and a pharmaceutically acceptable carrier. 268. A pharmaceutical composition comprising a compound of embodiment 192 and a pharmaceutically acceptable carrier. 269. Pharmaceutical composition, which contains a compound according to any of items 193 or 226-245 and a pharmaceutically acceptable carrier. 270. The pharmaceutical composition of any of embodiments 267-269, wherein the compound is in the form of a pharmaceutically acceptable salt. 271. The pharmaceutical composition of embodiment 270, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 272. The pharmaceutical composition of embodiment 271, wherein the pharmaceutically acceptable salt is a calcium salt. 273. Pharmaceutical composition according to any of paragraphs 267-272, which additionally contains the Compound

And or its pharmaceutically acceptable salt or deuterated derivative. 274. Pharmaceutical composition according to embodiment 273, in which the deuterated derivative of compound II is compound II. 275. Pharmaceutical composition according to any of paragraphs 267-272, which additionally contains (a) compound I and (B) compound I or its deuterated derivative. 276. Pharmaceutical composition according to embodiment 275, in which the deuterated derivative of compound II is compound II. 277. The compound according to any of embodiments 1-190 for use in the treatment of cystic fibrosis. 278. The compound according to embodiment 191 for use in the treatment of cystic fibrosis. 279. Compound according to variant 192 for use in the treatment of cystic fibrosis. 280. A compound according to any one of embodiments 193 or 226-245 for use in the treatment of cystic fibrosis. 281. The compound for use according to any of embodiments 277-280, wherein the compound is in the form of a pharmaceutically acceptable salt.

282. The compound for use according to embodiment 281, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 283. The compound for use according to embodiment 282, wherein the pharmaceutically acceptable salt is a calcium salt. 284. A compound for use according to any of paragraphs 277-283, wherein the treatment further comprises administration of Compound PI. 285. Compound for use according to any of paragraphs 277-283, in which treatment additionally includes administration of Compound PP1-a. 286. A compound for use according to any of paragraphs 277-283, wherein the treatment additionally includes the administration of Compound HER and Compound PP. 287. A compound for use according to any of paragraphs 277-283, wherein the treatment additionally includes the administration of Compound HER and Compound PI-a.

Other options include:

The compound of formula I: o ka (vp Z 1 cha Kk ) t

N

M o o KUN 2

From ve E (ka

Pharmaceutically acceptable salt of the compound of the formula o ka (part C 1 cha Kk ) t

N

M o o KUN 2

WITH

(ka and

Pharmaceutical composition containing: compound of formula I: o Kf (v2)p Z 1 cha Kk ) t

N

M o v On y

Kk p

With te E (ka and (i)) a pharmaceutically acceptable carrier.

The pharmaceutical composition according to variant implementation C, which additionally contains compound HER:

n vh ee

E o m sn (Kk) p.

A pharmaceutical composition according to variant implementation C, which additionally contains a pharmaceutically acceptable salt of compound II: n 7 СО en

E o m sn (Kk) p.

A pharmaceutical composition according to variant implementation C, which additionally contains compound PI: on (c) (c)

M

N

M

N

The pharmaceutical composition according to variant implementation C, which additionally contains a pharmaceutically acceptable salt of compound PI: on (c) (c)

M

N

M

N

Pharmaceutical composition according to embodiment 0, which additionally contains compound PI: on (c) (c)

M

N

M

N

A pharmaceutical composition according to an embodiment of the OO, which additionally contains a pharmaceutically acceptable salt of the PI compound:

he (in) (in)

M ss

M

N

The pharmaceutical composition according to the embodiment E, which additionally contains the PI compound: on (c) (c)

M ss

M

N

A pharmaceutical composition according to variant implementation E, which additionally contains a pharmaceutically acceptable salt of the compound HER: he (c) (c)

M su

M

N

A pharmaceutical composition that contains: a pharmaceutically acceptable salt of a compound of the formula I o ka (vp Z 1 cha Kk ) t

N

M

From 7

Kk p

With ve E (va pharmaceutically acceptable carrier.

The pharmaceutical composition according to the variant of the implementation of the GI, which additionally contains the compound I: n -x Os (6)

E E M sn (Kk) ol

A pharmaceutical composition according to its embodiment, which additionally contains a pharmaceutically acceptable salt of compound II:

Нн эх СО en

E o m sn (yuY3 sn

The pharmaceutical composition according to the variant of implementation of Y, which additionally contains compound Y: on (c) (c)

M

N

M

N

A pharmaceutical composition according to an embodiment of HER, which additionally contains a pharmaceutically acceptable salt of compound HER: he (c) (c)

M

N

M

N

The pharmaceutical composition according to the embodiment of M, which additionally contains the PI compound: on (c) (c)

M

N

M

N

A pharmaceutical composition according to variant implementation M, which additionally contains a pharmaceutically acceptable salt of the compound ІІ: he (c) (c)

M

N

M

N

A pharmaceutical composition according to variant M, which additionally contains compound PI:

he (in) (in)

M ss

M

N

A pharmaceutical composition according to variant implementation M, which additionally contains a pharmaceutically acceptable salt of compound PI: on (c) (c)

M su

M

N

A method of treating cystic fibrosis, which includes administering to a patient who needs it, a compound of the formula o ka (vp Z 1 cha Kk ) t

N

M o o KUN 2

WITH

4 (to the 4th

A method of treating cystic fibrosis, which includes administering to a patient in need of it a pharmaceutically acceptable salt of a compound of the formula o Kf (v2)p Z 1 cha Kk ) t

N

M o v On y

Kk p

From the E (unit

A method of treating cystic fibrosis, which includes administering to a patient in need of it a pharmaceutical composition containing: a compound of formula I:

o ka 2 Z 1 (vo ba e ) t

N

M cho r; ZHI 4 in (you) a pharmaceutically acceptable carrier.

The method of treating cystic fibrosis, which includes administering to a patient who needs it, a pharmaceutical composition containing: a pharmaceutically acceptable salt of a compound of the formula I o ka v2 C 1 (in m B) t

N

M

OO ef 4 3 (k 4 pharmaceutically acceptable carrier.

General experimental procedures

The definitions of some of the abbreviations in the following examples are summarized below:

Bos anhydride (Bos)20): di-tert-butyl dicarbonate

SI: carbonyldiimidazole pABSO: 1,4-diazabicyclo|2.2.2|octane

OB: 1,8-diazabicyclo(5.4.0)undec-7-ene

OSM: dichloromethane

IA: diisopropyl azodicarboxylate

PIEA (PIREA; M,M-diisopropylethylamine)

OMA: M,M-dimethylacetamide

DMF: M,M-dimethylformamide

DMSO: dimethyl sulfoxide

E2O: diethyl ether

EON: ethanol

NATI: hexafluorophosphate 1-|bis(dimethylamino)methylene-1H-1,2,3-triazolo|4,5-B|pyridinium-3- oxide hexafluorophosphate

IRA: isoproanol

Meon: methanol

MMP: M-methyl-2-pyrrolidone

MTBE: methyl tert-butyl ether

TV5-SI: tert-butyldimethylsilyl chloride

TFO: trifluoroacetic acid

From THF: tetrahydrofuran p-T5OH: p-toluenesulfonic acid

TRPO-PIAYUO complex: triphenylphosphine oxide complex with diisopropylazodicarboxylate

Reagents and starting materials were obtained from commercial sources unless otherwise stated and were used without purification. Proton and carbon NMR spectra were obtained either on a 400 MHz ETHNMR spectrometer VgykKeg Viozrip OKX, operating at a resonance frequency of 1H and 130

400 and 100 MHz, respectively, or on a 300 MHz NMR spectrometer. One-dimensional proton and carbon spectra were obtained using a wide-band observation probe (WBEO) with a sample rotation of 20 Hz and a digital resolution of 0.1834 and 0.9083 Hz/Pi, respectively. All proton and carbon spectra were obtained with temperature control at 30°C using standard previously published pulse sequences and standard processing parameters. The final purity of the compounds was determined using reversed-phase

HPLC using an Asdiyu OR S VEN C18 column (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umayeg5 (art.: 186002350) and a double gradient with a change of mobile phase B 1-99 95 for 3.0 minutes. Mobile phase A - H2HO (0.0595 SEZSO2H). Mobile phase B - SNZSM (0.035 96 SEZSO2H). The flow rate was 1.2 mL/min, the injection volume was 1.5 μL, and the column temperature was 60 °C. Final purity was calculated by averaging the area under the curve (AUC) of two UV curves (220 nm, 254 nm). Low-resolution mass spectra are presented as samples (MANI) obtained using a single-quadrupole mass spectrometer equipped with an electrospray ionization source (ESI) capable of providing a mass measurement accuracy of 0.1 Da and a minimum resolution of 1000 (no resolution units) in The optical purity of methyl (25)-2,4-dimethyl-4-nitropentanoate was determined by chiral gas chromatography (GC) analysis on an Adiepi 7890A/M5O 5975C instrument using a Kevek KI-VOEX5i (30 m x 0.25 mm x 0.25 μm a, with a flow rate of 2.0 ml/min (H2 carrier gas), at an injection temperature of 220 "C and a thermostat temperature of 120 "C, 15 minutes.

Synthetic examples

Synthesis of compound II: (K)-1-(2,2-difluorobenzoyl|94|(1,3)dioxol-5-yl)-M-(1-(2,3-dihydroxypropyl)-6-fluoro-2- (1-Hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)ucyclopropanecarboxamide

Ot5 3 KK

In HU and y pat s vvamsnya) s meon, But s-

US I on

Stage 1: (K)-benzyl-2-(1-(2,2-dimethyl-1,3-dioxolan-4-ylylmethyl)-6-fluoro-5-nitro-1H-indol-2-yl)- 2-methylpropanoate and / ((5)-2,2-dimethyl-1,3-dioxolan-4-yl)umethyl-2-(1-((H)-2,2-dimethyl-1,3-dioxolan- 4-yl)-methyl-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate

Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl-2-(b-fluoro-5-nitro-1H-indole-

of 2-yl)-2-methylpropanoate (3.0 g, 8.4 mmol) and (5)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-4-methylbenzenesulfonate (7, 23 g, 25.3 mmol) in DMF (M,M-dimethylformamide) (17 mL).

The reaction mixture was stirred at 80 "C for 46 hours under a nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over Mg5O4, filtered and concentrated. The crude product, viscous the brown oil containing both of the above products was sent directly to the next step without further purification.(K)-benzyl 2-(1-(2,2-dimethyl-1,3-dioxolan-4-yl)umethyl)-b -fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, MO-IER n/2 calcd. 470.2, found 471.5 (Ma1)-. Retention time 2.20 minutes. ( 5)-2,2-dimethyl-1,3-dioxolan-4-yl)umethyl 2-(1-((8)-2,2-dimethyl-1,3-dioxolan-4-yl)umethyl)-6 -Fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, MO-IER mp: calcd 494.5, found 495.7 (M-Al)k Retention time 2.01 minutes.

Stage 2: (K)-2-(1-(2,2-dimethyl-1,3-dioxolan-4-yl)umethyl)-6-fluoro-5-nitro-1H-indol-2-yl)- 2-methylpropan-1-ol

The crude reaction mixture obtained in step (A) was dissolved in THF (tetrahydrofuran) (42 mL) and cooled in an ice water bath. HyAIN4 (16.8 ml of 1 M solution, 16.8 mmol) was added dropwise. After the addition was complete, the mixture was stirred for another 5 minutes. The reaction was quenched by adding water (1 mL), 1595 Mahon solution (1 mL), and then water (3 mL). The mixture was filtered through celite and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by chromatography (30-60 9% ethyl acetate-hexanes) to obtain (K)-2-(1-

(2,2-dimethyl-1,3-dioxolan-4-yl)umethyl)-b-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol as a brown oil (2 .68 g, 87 9o for 2 herds). MO-IER t/72 calc. 366.4, found 367.3 (Ma1) . The retention time is 1.68 minutes. 1H NMR (400 MHz, OM5O-46) b 8.34 (y, 9 - 7.6 Hz, 1H), 7.65 (a, U - 13.4 Hu, 1H), 6.57 (5, 1H), 4.94 (I, U - 5.4 Hu , 1H), 4.64 - 4.60 (t, 1H), 4.52 - 4.42 (t, 2H), 4.16 - 4.14 (t, 1H), 3.76 - 3.74 (t, 1H), 3.63 - 3.53 (t, 2H), 1.42 (5, ZN), 1.38 - 1.36 (t, 6H) apa 1.19 (in,

ZN) parts/million (DMSO is dimethylsulfoxide).

Stage 3: (K)-2-(5-amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)umethyl)-6-fluoro-1H-indol-2-yl)-2 - methylpropan-1-ol (!)-2-(1-(2,2-dimethyl-1,3-dioxolan-4-yl)umethyl)-6-fluoro-5-nitro-1H-indole-2- yl)-2-methylpropan-1-ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL) and the reaction mixture was washed

M2. Then Ra-C (250 mg, 5 95 wt.) was added. The reaction mixture was again purged with nitrogen and then stirred under H2 (atm). In 2.5 hours, only a partial conversion to the product was observed by LCMS. The reaction was filtered through celite and concentrated. The residue was again subjected to the above conditions. In 2 hours, LCMS showed complete conversion to the product. The reaction mixture was filtered through celite. The filtrate was concentrated to give the product (1.82 g, 79 90). MO-IER t/2 calc. 336.2, found 337.5 (M.-1) w. The retention time is 0.86 minutes. IN NMR (400 MHz, OMZO-ab) 5 7.17 (d, U - 12.6 Hz, 1H), 6.76 (d, U - 9.0 Hz, 1H), 6.03 (s, 1H ), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 4.37-4.31 (m, ЗН), 4.06 (dd, U - 6.1, 8 ,3 Hz, 1H), 3.70-3.67 (m, 1H), 3.55-3.52 (m, 2H), 1.41 (s, ЗН), 1.32 (s, 6H) and 1.21 (c, ZN) parts/million.

Stage 4: (K)-1-(2,2-difluorobenzo|FChP,Z|dioxol-5-yl)-M-(1-(2,2-dimethyl-1,Z-dioxolan-4-ylylmethyl)- 6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)ucyclopropanecarboxamide

DMF (3 drops) was added to a stirred mixture of 1-(2,2-difluorobenzo|4|P1,3|dioxol-5-yl)ucyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL , 17.9 mmol). A clear solution was formed in 1 hour. The solution was concentrated in vacuo, then toluene (3 ml) was added and the mixture was concentrated again. The toluene step was repeated once more, and the residue was placed under high vacuum for 10 minutes. Then the hydrogen chloride was dissolved in dichloromethane (10 ml) and /(K)-2-(5-amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro was added to the mixture -1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL).

The reaction mixture was stirred at room temperature for 1 hour. Reaction mixture

It was washed with 1 n. NSI solution, saturated with Mansoz solution and saline solution, dried over

Mg5O4 and concentrated, obtaining the product (Z g, 100 95). MO-IER tp/2 calc. 560.6, found 561.7 (M-AT)zh. The retention time is 2.05 minutes. IN NMR (400 MHz, OM5O-a6) b 8.31 (5, 1H), 7.53 (5, 1H), 7.42 - 7.40 (t, 2H), 7.34 - 7.30 (t, ЗН), 6.24 (5, 1H), 4.51 - 4.48 (t, 1H), 4.39 - 4.34 (t.2H), 4.08 (aa, U - 6.0, 8.3 Hz, 1H), 3.69 (I, U - 7.6 Gu, 1H), 3.58 - 3.51 (t, 2H), 1.48 - 1.45 (t, 2H), 1.39 (5,

ЗН), 1.34 - 1.33 (t, 6Н), 1.18 (5, ЗН) apa 1.14 - 1.12 (t, 2Н) ppm.

Stage 5: (B)-1-(2,2-difluorobenzoyl|4|1,Z|dioxol-5-yl)-M-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1 - hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (8)-1-(2,2-difluorobenzoyl)-1,3-dioxol-5-yl)-M-(1- (2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)ucyclopropanecarboxamide ( 3.0 g, 5.4 mmol) was dissolved in methanol (52 ml). Water (5.2 mL) was added, followed by p-T5OH.H2O (p-toluenesulfonic acid hydrate) (204 mg, 1.1 mmol). The reaction mixture was heated at 80 "C for minutes. The reaction mixture was then evaporated at room temperature and partitioned between saturated aqueous Mansoze and ethyl acetate. The ethyl acetate layer was separated, dried over

Mg5O4, filtered and evaporated. The residue was purified by chromatography (50-100 906 ethyl acetate-45 hexanes) to obtain the product. (1.3 g, 47 96, ee" 98905 according to NKRKH). MO-IER t/2 calc. 520.5, found 521.7 (M.-1) w. The retention time is 1.69 minutes. T NMR (400 MHz, OM5O-ab) b 8.31 (5, 1H), 7.53 (5, 1H), 7.42 - 7.38 (t, 2H), 7.33 - 7.30 (t, 2H), 6.22 (5, 1H), 5.01 (a, y - 5.2 Hz, 1H), 4.90 (9 - 5.5 Hz, 1H), 4.75, U - 5.8 Hu, 1H), 4.40 (aa, U - 2.6, 15.1 Hu, 1H), 4.10 (aa, U - 68.7, 15.1 Hz, 1H), 3.90 (5, 1H), 3.65 - 3.54 (t, 2H), 3.48 - 3.33 (t, 2H), 1.48 - 1.45 (t, 2H), 1.35 (v, ЗН) , 1.32 (5,

ZN) apa 1.14 - 1.11 (t, 2H) parts per million.

Synthesis of compound PI: //M-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

Part A: Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (c) (c)

SS

M

N

Stage 1: 2-phenylaminomethylene diethyl ester of malonic acid

A mixture of aniline (25.6 g, 0.275 mol) and diethyl-2-(ethoxymethylene)malonate (62.4 g, 0.288 mol) was heated at 140-150 "C for 2 hours. The mixture was cooled to room temperature and dried under reduced pressure to obtain diethyl ether of 2-phenylaminomethylenemalonic acid in the form of a solid substance, which was used in the next stage without additional purification. 7.36-7.39 (t, 2H), 7.13-7.17 (t, ЗН), 4.17-4.33 (t, 4H), 1.18-1.40 (t, 6H).

Stage 2: 4-hydroxyquinoline-3-carboxylic acid ethyl ester

Diethyl ether of 2-phenylaminomethylene-malonic acid (26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g) were loaded into a three-necked flask with a volume of 1 L, equipped with a mechanical stirrer. The mixture was heated to 70 C and stirred for 4 hours.

The solution was cooled to room temperature and filtered. The residue was treated with an aqueous solution of Ma 2 СО 3 , filtered, washed with water and dried. Ethyl ether 4-hydroxyquinoline-

C-carboxylic acid was obtained as a pale brown solid (15.2 g, 70 Ub).

The crude product was used for the next step without further purification.

Stage 3: 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The ethyl ether of 4-hydroxyquinoline-3-carboxylic acid (15 g, 69 mmol) is suspended in a solution of sodium hydroxide (2 N, 150 ml) and stirred for 2 hours under reflux. After cooling, the mixture was filtered and the filtrate was acidified to pH 4 with 2 n. NSI The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 90). IN NMR (0M50-a6) b 15.34 (5, 1 H), 13.42 (5, 1 H), 8.89 (5, 1H), 68.28 (a, y -8.0 Gu, 1H), 7.88 (t, 1H), 7.81 (a, U - 8.4 Hu, 1H), 7.60 (t, 1H).

Part B: Synthesis of /N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

SISO, Me nMO,, N.O,

MEB, LOBSTER om o o on sni, o 2 oo ogo still eat con, meon ---lel' 77khxB and om on on

MO, nsOo MN, -- incl

Ra-s, EUON om on Nam on

Stage 1: methyl ester of 2,4-di-tert-butylphenyl ether of carbonic acid.

Zo Methyl chloroformate (58 ml, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butylphenol (103.2 g, 500 mmol), EIZM (139 ml, 1000 mmol) and OMAR (3.05 g, 25 mmol) ) in dichloromethane (400 mL) was cooled in an ice-water bath to 0 "C. The mixture was allowed to warm to room temperature with stirring overnight, then filtered through silica gel (approximately 1 L) using 10 95 ethyl acetate-hexanes (- 4 L ) as an eluent. The combined filtrates were concentrated to obtain the methyl ether of 2,4-di-tert-butylphenyl ether of carbonic acid in the form of a yellow oil (132 g, quantity). IN NMR (400 MHz, OM5O-4a6) b 7.35 ( y, 9 - 2.4 Hz, 1H), 7.29 (aa, U - 8.5, 2.4 Hz, 1H), 7.06 (a, U - 8.4 Hz, 1H), 3.85 (5, ЗН), 1.30 (5, 9H), 1.29 (5, 9H).

Stage 2: methyl ester of 2,4-di-tert-butyl-5-nitro-phenyl ether of carbonic acid and methyl ester of 2,4-di-tert-butyl-6-nitro-phenyl ether of carbonic acid.

To a stirred mixture of carbonic acid, 2,4-di--tert-butyl-phenyl ether, methyl ether (4.76 g, 180 mmol) in conc. of sulfuric acid (2 ml), cooled in a bath with ice and water, a cooled mixture of sulfuric acid (2 ml) and nitric acid (2 ml) was added.

The addition was made slowly so that the reaction temperature did not exceed 50 es.

The reaction mixture was stirred for 2 h when heated to room temperature. Then the reaction mixture was added to ice water and extracted into diethyl ether. The ether layer was dried (Mg5O4), concentrated and purified by chromatography (0-10 95 ethyl acetate-hexanes) to obtain a mixture of methyl ester of 2,4-di-tert-butyl-5-nitro-phenyl ether of carbonic acid and methyl ester of 2,4- di-tert-butyl-b-nitro-phenyl ether carbonic acid as a pale yellow solid (4.28 g), which was used directly in the next step.

Stage 3: 2,4-di-tert-butyl-5-nitro-phenol and 2,4-di-tert-butyl b-nitro-phenol

A mixture of methyl ester of 2,4-di-tert-butyl-5-nitrophenyl ether of carbonic acid and methyl ester of 2,4-di-tert-butyl-6-nitrophenyl ether (4.2 g, 14.0 mmol) was dissolved in

Meon (65 mL) before adding KOH (2.0 g, 36 mmol). The mixture was stirred at room temperature for 2 h. Then the reaction mixture was acidified (pH 2-3), adding conc. NSI and partitioned between water and diethyl ether. The ether layer was dried (Mg50O4), concentrated and purified by chromatography (0-595 ethyl acetate-hexanes) to give 2,4-di-tert-butyl-5-nitrophenol (1.31 g, 29 95 over 2 stages) and 2.4 -di-tert-butyl-b-nitrophenol. 2,4-di-tert-butyl-

B-nitrophenol: 1H NMR (400 MHz, OM5O-a6) 5 10.14 (5, 1H, OH), 7.34 (5, 1H), 6.83 (5, 1H), 1.36 (5, 9H), 1.30 (5, 9H ). 2,4-0i--ep-bshuI-6-pigo-rpepoi!: IN NMR (400 MHz, SOSIS) b 11.48 (5, 1H), 7.98 (a,

U - 2.5 Hz, 1H), 7.66 (y, U - 2.4 Hz, 1H), 1.47 (5, 9H), 1.34 (5, 9H).

Stage 4: 5-amino-2,4-di-tert-butyl-phenol

To a refluxing solution of 2,4-di-tert-butyl-5-nitrophenol (1.86 g, 7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Ra -5 95 wt. on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature and filtered through celite. Celite was washed with methanol and the combined filtrates were concentrated to give 5-amino-2,4-di-tert-butylphenol as a gray solid (1.66 g, qty.). TIA NMR (400 MHz, OM5O-a6) b

Зо 8.64 (5, 1Н, ОН), 6.84 (5, 1Н), 6.08 (5, 1Н), 4.39 (5, 2Н, МНЗгаб) b 8.64 (5, 1Н, ОН), 6.84 (5, 1Н), 6.08 (5, 1Н), 4.39 (5, 2Н, МН), 1.27 (t, 18Н); TOP time. morning 2.72 min., 10-99 95 SNZSM, 5 min. processing;

MO-0ER 222.4 t/z; (Mani k.

Stage 5: M-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (c) on tre (o) sor» 0-0 du

M nem he so

N | (at)

M

NN

To a suspension of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (35.5 g, 188 mmol) and NVTI (85.7 g, 226 mmol) in DMF (280 mL) was added 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before adding 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) in small portions. The mixture was stirred overnight at ambient temperature.

During the reaction, the mixture became heterogeneous. After all the acid has been consumed (analysis

LC-MS, МН190, 1.71 min), the solvent was removed under vacuum. EN (ethyl alcohol) was added to the orange solid to obtain a suspension. The mixture was stirred on a rotary evaporator (bath temperature 65 C) for 15 min, without placing the system in a vacuum. The mixture was filtered and the trapped solid was washed with hexane to give a white solid which was a crystal of EN. E12O (diethyl ether) was added to the solid obtained above to form a suspension. The mixture was stirred on a rotary evaporator (bath temperature 25 "C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid was captured. This procedure was performed a total of five times.

The solid obtained after the fifth precipitation was placed under vacuum overnight to obtain

M-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52 95). TOP time. morning 3.45 min., 10-99 95 SNZSM, 5 min. processing; 1TH NMR (400 MHz, OM5O-ab6-ab) b 12.88 (5, 1H),

11.83 (5, 1H), 9.20 (5, 1H), 8.87 (5, 1H), 8.33 (aa, U - 8.2, 1.0 Hz, 1H), 7.83-7.79 (t, 1H), 7.76 (y,

U - 7.7 Hz, 1H), 7.54-7.50 (t, 1H), 7.17 (5, 1H), 7.10 (5, 1H), 1.38 (5, 9H), 1.37 (5, 9H); MO-IER t/7 calc. 392.21; found 393.3 MANI k.

Synthesis of compound IM: 3-(6-(1-(2,2-difluorobenzoid4|/1,3|dioxol-5-yl)ucyclopropanecarboxamido)-3-methylpyridin-2-yl/benzoic acid

The IM compound can be obtained by linking the chloride fragment with the amine fragment according to the schemes from IM-A to IM-O.

IM-A scheme. Synthesis of the chloride fragment.

E o 1. Restoration iv) 1.80s, g o

ХХ te 2 pcs 2. MDaON on 2. no E o SI oo son be 1. masm 2.nNO g O (c) ВH

Z Ii maon X ta ko -T6-25 cm 7 » oo on ho kon ko cm osi,

B o o o o si

Scheme IM-A shows the preparation of 1--2,2-difluorobenzoi|9ch|Y,Z|dioxol-5-yl)ucyclopropanecarbonyl chloride, which is used in scheme IM-C to form the amide bond of compound IM.

The starting material, 2,2-difluorobenzoi9h|(1,3|dioxol-o-carboxylic acid, is commercially available from Zako (a subsidiary of Iaphe55 Sogrogayop). Reduction of the carboxylic acid fragment in 2,2-difluorobenzoi|4|/1,Z| of dioxole-5-carboxylic acid to the primary alcohol followed by conversion to the corresponding chloride using thionyl chloride (ZOSI 2) gives 5-(chloromethyl)-2,2-difluorobenzoi|d9|1,3|dioxole, which is then converted into 2- ( 2,2-difluorobenzoi|4|(1,3)dioxol-5-yllauacetonitrile with the addition of sodium cyanide. with chloroethane gives 1-(2,2-difluorobenzoyl|Y,Z|dioxol-5-yl)ucyclopropanecarbonitrile. The nitrile fragment in 1-(2,2-difluorobenzoyl|Y,Z|dioxol-5-yl)ucyclopropanecarbonitrile is converted into a carboxylic acid

With the use of the base With the receipt of 1--2,2-difluorobenzoi|94|/1,3|dioxol-5-yl)ucyclopropanecarboxylic acid, which is converted into the desired chloride anhydride using thionyl chloride.

IM-V scheme. Alternative synthesis of the chloride fragment.

E IF) is) Ras(aba)»", I-VozR E IF) o same and A osm same go Ve EYU MazRo,, GO OEi

Topepe, NoO, 70 C SM

WITH M NOSE,

ORM5O, 159 rooms! at

EE about E SM

Mahon and);

You MVg 1. Maon 2. NOI me o 5OSI, E I. o - - - t

Go On go SI

Scheme IM-B depicts an alternative synthesis of the necessary chloride. 5-bromomethyl-2,2-difluoro-1,3-benzodioxol is combined with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha-cyanoethyl ether. Saponification of the ester part to a carboxylic acid gives the cyanoethyl compound IM. Alkylation of a cyanoethyl compound with 1-bromo-2-chloroethane in the presence of a base gives a cyanocyclopropyl compound. Treatment of a cyanocyclopropyl compound with a base gives a carboxylate salt, which is converted to a carboxylic acid by acid treatment. The conversion of the carboxylic acid to the chloride is then carried out using a chlorinating agent such as thionyl chloride, etc.

IM-S scheme. Synthesis of the amino group. sia (NO)»V 2. ad. MeOH what

SS we IF 3. ad. Mahon

M Vg

OWLS from OWLs igea-pudgorep regohide rishans apruahide

EsOAs, mageg

And Mr. M

I. MeO,ru,MesM "

SOIVY 2. eshapoYIatipe o. OWL

Scheme IM-C shows the preparation of the necessary tert-butyl-3-(6b-amino-3-methylpyridin-2-yl)benzoate, which combines with 1--2,2-difluorobenzoi|4|/1,Z|dioxol- 5-

with yl)ucyclopropanecarbonyl chloride on the IM-C scheme to obtain compound IM. Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonylphenylboronic acid) gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is then converted to the desired compound.

Im-0 scheme. Formation of the acid salt of 3-(6-(1-(2,2-difluorobenzoi94|(/1,3|dioxol-5-ylylcyclopropanecarboxamido)-3Z-methylpyridin-2-yl)benzoic acid. i, 5,sa

H o. | . TEA, sa OMAR Be o db eE o si nm M E o m s

M

OWLs live in Asia

XX o and th mm

Mt Asiy Sol

Scheme d) depicts the coupling of 1--2,2-difluorobenzoi|4|1I1,3|dioxol-5-ylylcyclopropanecarbonyl chloride with tert-butyl-3-(6b-amino-3-methylpyridin-2-yl)benzoate using triethylamine and 4 of dimethylaminopyridine for the initial preparation of tert-butyl ether of compound IM.

Syntheses of compounds

General analytical methods of HPLC/HPLC:

Unless otherwise stated, yields of enantiomers resolved by chiral NPCR are given as a percentage of the theoretical yield for one enantiomer of the racemate.

Method of LC A: analytical reversed-phase HPLC using an Asdiyu ORI S column

VEN C18 (30 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002349), and a double gradient with a change in mobile phase B 1-99 95 for 1.2 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 95 trifluoroacetic acid). The flow rate is 1.5 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

RH method B: analytical reversed-phase HPLC using an Asdiyu ORI S column

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 1-99 95 for 3.0 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 96 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

Method РХ C: Analytical HPLC with reversed phase using a Kipeich C18 column (50x3.0 mm) and run with a double gradient from 5-100 96 mobile phase B for b minutes.

The mobile phase A is water (0.1 956 trifluoroacetic acid). Mobile phase B - acetonitrile (0.1 Fo trifluoroacetic acid). The flow rate is 1.5 ml/min, the injection volume is 2 μl, and the column temperature is 30 °C.

РХ method: analytical reversed-phase HPLC using an Asdiyu ORI S column

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 1-99 95 for 5.0 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 95 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

Method of РХ E: analytical reversed-phase HPLC using an Asdiyu ORI S column

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 1-99 95 for 2.5 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 95 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

Method of LC EE: analytical reversed-phase HPLC using an Asdiyu column FIG

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 1-99 95 for 15.0 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 95 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

Method РХ 0: analytical reversed-phase HPLC using an Asdiyu ORI C column

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 30-99 95 for 3.0 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 96 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

ІС Method H: Kipeiech C 18 4.6 x 50 mm 2.6 microns. Temperature: 45 "C, flow: 2.0 ml/min, run time: b min. Mobile phase: initial 95 95 water (0.1 965 formic acid) and 5 95 acetonitrile (0.1 96 formic acid), linear gradient to 95 95 acetonitrile (0.1 96 formic acid) for 4.0 min, then hold at 95 95 acetonitrile (0.1 956 formic acid) for 2.0 min.

Method РХ I: Kipeyeh C 18 4.6 x 50 mm 2.6 microns. Temperature: 45 "C, flow: 2.0 ml/min, running time: 3 min. Mobile phase: initial 95 95 water (0.1 95 formic acid) and 5 95 acetonitrile (0.1 96 formic acid), linear gradient to 95 95 acetonitrile (0.1 96 formic acid) for 2.0 min, then hold at 95 95 acetonitrile (0.1 96 formic acid) for 1.0 min.

The LC method in: analytical reversed-phase HPLC using an Asdiyu column FIG

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 50-99 95 for 3.0 minutes. Mobile phase A is water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 95 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

The method of РХ K: analytical reversed-phase HPLC using an Asdiyu ORI S column

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 30-99 95 for 1.0 minutes. Mobile phase A -

From water (0.05 96 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 96 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

Method РХ I: analytical reverse-phase HPLC using an Asdiyu ORI S column

VEN C18 (50 x 2.1 mm, 1.7 μm particle size) manufactured by Umaieg5 (art.: 186002350), and a double gradient with a change in mobile phase B 50-99 905 for 1.0 minutes. Mobile phase A - water (0.05 95 trifluoroacetic acid). Mobile phase B - acetonitrile (0.035 96 trifluoroacetic acid). The flow rate is 1.2 ml/min, the injection volume is 1.5 μl, and the column temperature is 60 s.

Method РХ M: analytical reversed-phase HPLC using a Kipeyech C18 column (50x3.0 mm) and running with a double gradient from 5-100 95 mobile phase B for 6 min. Mobile phase A is water (0.195 trifluoroacetic acid). Mobile phase B - acetonitrile (0.195 trifluoroacetic acid). The flow rate is 1.5 ml/min, the injection volume is 10 μl, and the column temperature is 30 °C.

Method РХ M: 7ogra C18 4.6 x 50 mm 3.5 μm. Flow: 2.0 mL/min, gradient 95 95 water (0.1 95 trifluoroacetic acid) w- 55905 acetonitrile (0.195 trifluoroacetic acid) to 9595 acetonitrile (0.1 96 trifluoroacetic acid) (2.0 min), then hold at 95 95 acetonitrile (0.1 to trifluoroacetic acid) for 1.0 min.

Method РХ О: 7ogra 5В-С18 4.6 x 50 mm 3.5 μm, temperature: 45 "C, flow 2.0 ml/min, holding time: 4 min. Mobile phase conditions: initial 95 9o of water (0, 1 96 formic acid) and 5 95 acetonitrile (0.195 formic acid) linear gradient to 95905 acetonitrile (0.1 95 formic acid) for 2.0 min, then hold at 95 95 acetonitrile (0.1 96 formic acid) for 2. 0 min.

Method РХ R: column MegsoKipiroge Spgotoiy breeeakKOI C18 (50 x 4.6 mm) and running with a double gradient from 5-100 96 mobile phase B for b minutes. Mobile phase A is water (0.19% trifluoroacetic acid). Mobile phase B - acetonitrile (0.1 95 trifluoroacetic acid).

Method РХ 0: column MegoKipiiyroge Spgotoiypy ZreeeakKOYU C 18 (50 x 4.6 mm) and run with a double gradient from 5-100 96 mobile phase B for 12 minutes. Mobile phase A is water (0.1 95 trifluoroacetic acid). Mobile phase B - acetonitrile (0.1 95 trifluoroacetic acid).

RH EC method: UmMaiege Sogieh 2.7 μm C18 (3.0 mm x 50 mm), temperature: 55 "C; flow rate: 1.2 bo ml/min; Mobile phase A: 100 90 water with 0.1 96 trifluoroacetate acid Mobile phase B: 100 96 acetonitrile with 0.196 trifluoroacetic acid Gradient: 5956 to 10095 V for 4 min, holding at 100 95 V for 0.5 min, equilibrating to 5 90 V for 1.5 min.

Method РХ 5: Horn singing! 120 ES-C18 3.0 x 50 mm 2.7 µM, temperature: 45 "C, flow: 2.0 ml/min, working time: 6 min. Mobile phase conditions: initial 95 95 water (0.1 95 trifluoroacetic acid) and 5 95 acetonitrile (0.1 90 trifluoroacetic acid), linear gradient to 95 95 acetonitrile (0.1 95 trifluoroacetic acid) for 4.0 min, then hold in 95905 acetonitrile (0.1 95 trifluoroacetic acid) for 2 ,0 min.

РХ T method: 2 ogra C18 4.6 x 50 mm 3.5 μM, Zesygu Stsag: ASHCHO-4287 C 18, 4 x 3.0 mm.

Temperature: 45 "C, flow: 2.0 ml/min, run time: 6 min. Mobile phase: 95 95 water (0.1 95 formic acid) and 5 95 acetonitrile (0.1 96 formic acid), linear gradient to 95 95 acetonitrile (0.1 96 formic acid) for 4.0 min, then holding for 2.0 min.

Method of RH M: Kipeieh EMO C18 4.6 8. times; 50 mm, 2.6 µm, temperature: 45 "C, flow rate: 2.0 ml/min, running time: 4 min. Mobile phase: initial 9595 water (0.1 95 formic acid) and 5 95 acetonitrile (0.195 formic acid) linear gradient to 95905 acetonitrile (0.1 95 formic acid) for 2.0 min, then extraction at 95 95 acetonitrile (0.1 96 formic acid) for 2.0 min.

Example 1: Preparation of 12,12,19-trimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11 ,19,24-pentaazatetracyclo|18.3.1.05,10.011,15|)tetracose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 9) in ) o cm soy em? ой (о) Zer2 0 K o cholo goda y v s so svevs u sere S nn

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Stage 1: tert-butyl 2,6-dichloropyridine-3-carboxylate (o) (o)

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A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in tetrahydrofuran (210 mL) was treated sequentially with di-tert-butyldicarbonate (17 g, 77.9 mmol) and 4-(dimethylamino)pyridine ( 3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this moment, 1 n. was added. hydrochloric acid (400 mL) and the mixture was vigorously stirred for about 10 minutes. The product was extracted with ethyl acetate (2 x 300 mL) and the combined organic layers were washed with water (300 mL) and brine (150 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to give 12.94 g (96 95 yield) tert-butyl 2,6-dichloropyridine-3-carboxylate in the form of a colorless oil. 1H NMR (300

MHz, SOSIZ) 5 1.60 (5, 9H), 7.30 (a, 9U-7.9 Hz, 1H), 8.05 (y, 9-8.2 Hz, 1H). MO-IER t/2 calc. 247.02, found 248.1 (M--1)k; Holding time: 1.79 min. (Method of RH B).

Stage 2: tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (c) o M o

Zoo with and 5 0-4-

A 50-liter reactor was started, and the jacket was set at 20 "С, with stirring at a speed of 150 rpm under a dephlegmator (10 "С) and nitrogen purging. Methanol (2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added and the reactor was closed. The reaction mixture was heated to an internal temperature of 40 °C, and the system was set to maintain a jacket temperature of 40 °C. Hydrazine hydrate (1300 g, 55 95 wt., 22.31 mol) was added in portions through a dropping funnel over 30 min. The reaction mixture was heated to 60 °C for 1 hour.

The reaction mixture was cooled to 20 "С and triethylamine (2.483 kg, 3.420 L, 24.54 mol) was added in portions, maintaining the reaction temperature at 30 "С. A solution of Bos anhydride (4.967 kg, 5.228 L, 22.16 mol) in methanol (2.860 L) was added in portions, maintaining the temperature at 45 76.

The reaction mixture was stirred at 20 "C for 16 h. The reaction solution was partially concentrated to remove methanol, resulting in a clear, light amber-colored oil. The resulting oil was transferred to a 50 L reactor, stirred, and water (7.150 L) and heptane ( 7.150 L). Additives caused a small amount of product to precipitate. The aqueous layer was poured into a clean container, and the interface and heptane layer were filtered to

From the solid matter (product) department. The aqueous layer was transferred back to the reactor and the collected solid was placed back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and acetic acid (1.474 kg, 1.396 L, 24.54 mol) was added dropwise. The jacket was set at 0 "C to absorb the exothermic quenching reaction. After the addition was complete (pH - 5), the reaction mixture was stirred for 1 hour. The solid was collected by filtration and washed with water (7.150 L), then washed a second time with water (3.575 L). The crystalline solid the substance was transferred to a flask with a rotary valve for 20 liters, heptane (7.150 liters) was added. The mixture was suspended at 45 "C for 30 minutes and 1-2 volumes of the solvent were distilled off. The suspension in a rotary evaporator flask was filtered and the solids were washed with heptane (3.575 L). The solid was further dried in a vacuum (50 "С, 15 mbar) to obtain tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (2921 g, 7195) in the form of a large crystalline solid. IN NMR (400 MHz, DMSO-ab) b 10.95 (5, 1H), 7.98 (a, U - 2.9 Hz, 1H), 5.90 (a, U - 2.9 Hz, 1H), 1.54 (5, 9H).

Stage 3: 2-benzylsulfanyl-6-fluoropyridine

- - and Em Shi 2,6-difluoropyridine (200 g, 1.738 mol) was dissolved in dimethyl sulfoxide (2 L) in a 5 L three-neck round-bottom flask equipped with a hanging stirrer, a temperature sensor, and a dropping funnel. Cesium carbonate (572.4 g, 1.757 mol) was added. Phenylmethanethiol (206 mL, 1.755 mol) was added dropwise through the dropping funnel. An exothermic effect was observed during the addition. The temperature rose to about 40 "C. The reaction was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The extract was washed twice with water and filtered through a small pad of silica gel. The plug was eluted with dichloromethane and the filtrate was evaporated in vacuo to give 2-benzylsulfanyl-b -fluoropyridine (366 g, 96 95) as a peach-colored oil which solidified in vacuum to large block plates.IN NMR (400 MHz, chloroform-4) b 7.58 (q, U - 7.9 Hz, 1H) , 7.48-7.41 (m, 2H), 7.36-7.25 (m, 4H), 7.06 (dd, U - 7.6, 2.1 Hz, 1H), 6.62 (dd, U - 7.9, 2.6 Gu, 1H), 4.43 (c, 2H).

Stage 4: b6-fluoropyridine-2-sulfonamide uv uv ----- to which m i oo 2-benzylsulfanyl-b-fluoropyridine (303.2 g, 1.383 mol) was dissolved in chloroform (2.0 L) in a three-necked round-bottom a 12-liter flask equipped with a hanging stirrer and a temperature sensor.

Water (1.5 L) was added and the mixture was cooled in an ice bath to 0 C and stirred intensively. Chlorine gas from the cylinder was vigorously bubbled into the reaction using a Pasteur pipette inserted through the septum on the third neck of the flask. A white precipitate formed rapidly. An exothermic effect was observed during the addition. Chlorine addition was stopped when the temperature rose to 20°C. The reaction mixture was allowed to cool again before more chlorine gas was added. Dosing was continued until the reaction turned yellowish-green and remained so after stirring for 30 minutes.

At this point, no additional exotherm was observed. The reaction mixture was poured into a solution of 40 95 aqueous sodium bisulfite. The organic layer was separated, and the aqueous layer was extracted with another portion of chloroform. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a slightly yellow oil. The oil was dissolved in dichloromethane (1.5 L) and added dropwise to ammonium hydroxide (1.5 L, 40 95 wt./Vol., 17.12 mol) in a 12 L three-necked round-bottom flask equipped with a hanging stirrer, a temperature sensor and an additional watering can. Before addition, the ammonium hydroxide solution was cooled to 0 °C in an ice bath. The rate of addition was adjusted so that the reaction temperature remained below 10 °C. The resulting greenish-yellow solution was stirred for an hour and poured onto ice. The layers were separated (the organic layer was dark green) and the aqueous layer was further extracted with dichloromethane. The organic layers were removed. The aqueous layer was cooled in an ice bath and concentrated aqueous hydrochloric acid was added portionwise to the aqueous layer until the pH became strongly acidic. The resulting mixture was stirred as each portion was added. The obtained aqueous solution was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a light brown solid. The solid was mixed with dichloromethane (approximately 500 mL) and stirred with a magnetic stirrer until most of the large lumps were broken up. About 1.5 L of pentane was added, resulting in a large precipitate of a light brown solid.

The resulting mixture was quickly stirred and then filtered. The precipitate on the filter was washed with pentane and dried under vacuum to obtain 6b-fluoropyridine-2-sulfonamide (204.1 g, 84 Fo) as a light brown solid. 1H NMR (300 MHz, DMSO-ab) 5 8.52 - 8.11 (t, 1H), 7.89 (ai, U - 7.68, 2.7 Hz, 1H), 7.67 (5, 2H), 7.57 - 7.44 (t, 1H).

Stage 5: 2-/1-(trifluoromethyl)cyclopropyl|ethanol

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2-(/1-(trifluoromethyl)cyclopropyl|acetic acid (1.002 g,

5.948 mmol) in tetrahydrofuran (3.0 mL) for 30 min, maintaining the reaction temperature below 20 °C. The reaction mixture was allowed to gradually warm to ambient temperature and stirred for 18 h. The mixture was cooled in an ice bath and quenched successively with water (294 mg , 295 μL, 16.36 mmol), sodium hydroxide (297 μL 6 M, 1.784 mmol) and then water (884.0 μL, 49.07 mmol) to give a granular solid in the mixture. The solid was filtered using celite, and the precipitate was washed with ether.

The filtrate was additionally dried with magnesium sulfate, filtered, and concentrated by mass to obtain a product with residual tetrahydrofuran and ether. The mixture was transferred to the next stage without additional purification.

Stage 6: tert-butyl 3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1-carboxylate (c) o. , at 0-4-

tert-Butyl 5-oxo-1H-pyrazole-2-carboxylate (1.043 g, 5.660 mmol), 2-p1-(trifluoromethyl)cyclopropyl ethanol (916 mg, 5.943 mmol) and triphenylphosphine (1.637 g, 6.243 mmol) vol. were combined in tetrahydrofuran (10.48 ml) and the reaction mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (1.288 g, 1.254 mL, 6.368 mmol) was added dropwise to the reaction mixture and the reaction mixture was allowed to warm to room temperature over 16 hours.

The mixture was evaporated, and the resulting material was partitioned between ethyl acetate (30 mL) and 1 N. sodium hydroxide (30 ml). The organic layer was separated, washed with saline solution (30 ml), dried over sodium sulfate and concentrated. The crude substance was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane (0-30 95), to obtain tert-butyl-3-(2-P-trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1-carboxylate (1.03 g, 5795). MO-IER t/: calc. 320.13, found 321.1 (M-n1) k; Holding time: 0.72 min. (Method of RH A).

Stage 7: 3-(2-11-"trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (e) E M

Bk o- A. same kt "MNO STRA

Kt Ma, c) E

tert-Butyl-3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1-carboxylate (1.03 g, 3.216 mmol) was dissolved in dichloromethane (10.30 mL) with trifluoroacetic acid (2.478 mL, 32, 16 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, and the resulting oil was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, and dried

Zo over sodium sulfate and evaporated to give 3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (612 mg, 86 95). 1N NMR (400 MHz, DMSO-ab) b 11.86 (5, 1H), 7.50, 9 - 2.1 Hu, 1H), 5.63 (092.3 Hz, 1H), 4.14, 9 - 7.1 Hz, 2H), 2.01 (1, U - 7.1 Hu, 2H), 0.96 - 0.88 (t, 2H ), 0.88 - 0.81 (t, 2H). MO-IER t/ calc. 220.08, found 221.0 (M--1)k; Holding time: 0.5 min. (Method of RH A).

Stage 8: tert-butyl 2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylate) 20-- My wound Kk va E 0-5 Me

IS

B

tert-butyl 2,6-dichloropyridine-3-carboxylate (687 mg, 2.770 mmol), 3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (610 mg, 2.770 mmol) and freshly ground potassium carbonate (459 mg, 3.324 mmol) was combined in anhydrous dimethyl sulfoxide (13.75 mL).

1,4-diazabicyclo|2.2.2|octane (62 mg, 0.5540 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (20 ml) and stirred for 15 min. The resulting solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and concentrated to obtain tert-butyl-2-chloro-6-I(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylate (1.01 g, 84 95). MO-IER t/2 calcd. 431.12, found 432.1 (M'-1); Retention time: 0.88 min. (Method RH A).

Stage 9: 2-Chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid o) i) and ok and he is 0-5 MS is 0-5

E E ko Mk

Tert-butyl-2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylate (1.01 g, 2.339 mmol) and trifluoroacetic acid (1, 8 ml, 23.39 mmol) were combined in dichloromethane (10 ml) and heated at 40 °C for 3 hours. The reaction mixture was concentrated.

Hexanes were added and the mixture was concentrated again to obtain /2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (873 mg, 99 95)

MO-ER t/2 calc. 375.06, found 376.1 (M'-1)k; Holding time: 0.69 min. (Method of RH A).

Stage 10: tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate n Bos

M M pH 7 but 5,5-dimethylpyrrolidin-2-one (4.77 g, 42.1 mmol), 4-M,M-dimethylaminopyridine (9.19 g, 421 mmol) and triethylamine (4.26 g, 42.1 mmol) was dissolved in anhydrous dichloromethane (140 ml), then di-tert-butyl dicarbonate (27.6 g, 0.126 mol) was added. The reaction mixture was stirred at room temperature for 48 h. The reaction solution was diluted with dichloromethane (500 ml), washed with 1 n. aqueous solution of hydrogen chloride (100 ml) and saline solution (2 x 50 ml).

The organic layers were dried over magnesium sulfate, filtered and concentrated. The resulting residue was subjected to chromatography on silica gel using a hexane-ethyl acetate gradient method (from 0 to 2095 ethyl acetate in hexane) to obtain tert-butyl-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (5.48 g, 58 95 ) as a white solid. 1H NMR (250MHz,

SOSIZ) 6 2.48 (I, 7 - 8.0Hz, 2H), 1.85 (I, 7 - 8.0Hz, 2H), 1.54 (5, 9H), 1.47 (5, 6H). MO-IER t/2 calc. 213.1, found 214.1 (M'-1)khk. Holding time: 2.36 min. (Method of RH C).

Stage 11: tert-butyl-5-allyl-2,2-dimethylpyrrolidine-1-carboxylate

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Tert-butyl-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (2.72 g, 12.8 mmol) was dissolved in anhydrous ether (36 mL) and anhydrous tetrahydrofuran (36 mL) and then cooled to -78706 Diisobutylaluminum hydride (14.1 mmol, 14 ml, 1.0 M in toluene) was slowly added to the above solution, and the resulting solution was stirred at -78 °C for 4 hours, then warmed to room temperature and further stirred for 3 hours. Then, p-toluenesulfonic acid monohydrate (18 mg) in methyl alcohol (40 mL) was added and the resulting solution was stirred for 19 h.All solvents were removed under reduced

From pressure. A saturated aqueous solution of sodium potassium tartrate (100 ml) was added to the resulting residue and stirred for 3 hours. The solution was extracted with diethyl ether (3 X 150 ml).

The combined organic layers were washed with brine (2 x 50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the intermediate compound as a pale yellow oil (2.65 g). This intermediate and allyltrimethylsilane (2.34 g, 20.5 mmol) were dissolved in anhydrous dichloromethane (60 mL) and cooled to -78 °C. Boron trifluoride diethyl etherate (1.72 g, 12.1 mmol) was then slowly added. After completion of the addition, the reaction solution was stirred at -78 "С for 2 hours, and then for another 2 hours at room temperature. A 1 M aqueous solution of potassium carbonate (25 ml) was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 X 60 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel using a gradient method of hexane-ethyl acetate (from 0 to 15 95 ethyl acetate) to obtain tert-butyl-5-allyl-2,2-dimethyl-pyrrolidine-1-carboxylate (0.92 g, 30 95 ) in the form of a colorless oil. IN NMR (250MHz, SOSIZ) b 5.76 (t, 1H), 5.08-5.01 (t, 2H), 3.94-3.82 (t, 1H), 2.43 (t, 1H), 2.13 (t, 1H), 2.00 (t , 2H), 1.70 (t, 2H), 1.57 (5, 9H), 1.41 (5, ЗН), 1.28 (5, ЗН). MO-

IER t/2 calc. 239.2, found 240.1 (M.-1)k. Holding time: 3.83 min. (Method of RH C).

Stage 12: tert-butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate

9-BVM (15.38 mmol, 30 .8 ml, 0.5 M in tetrahydrofuran).The resulting solution was stirred at room temperature for 3 hours.

The reaction solution was cooled to 0 "С, an aqueous solution of hydrogen peroxide (38.5 mmol, 4.4 ml, 30 95 in water) was added, and then sodium hydroxide (19.25 mmol, 3.9 ml, 20 95 in water) After that, the reaction mixture was stirred at room temperature for 1.5 h. Water (50 ml) was added, and the aqueous solution was extracted with diethyl ether (4 x 80 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using hexanes and ethyl acetate (from 0 to 35 95 ethyl acetate in hexane) to give tert-butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (834 mg, 8495) in the form of a colorless oil. 1H NMR (250 MHz, DMSO) b 4.39 (t, 1H), 3.67 (t, 1H), 3.37 (t, 2H), 1.88-1.49 (t, 6H), 1.40 (5 . min. (Method RH C).

Stage 13: tert-butyl-2,2-dimethyl-5-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate. that's mine)

M -- 6 Ж5-4-5- M /В ох

Tert-butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (3.5 g, 13.6 mmol) and triethylamine (3.8 mL, 27.2 mmol) were dissolved in 40 mL of dichloromethane and cooled in an ice bath. Methanesulfonyl chloride (1.2 mL, 15.0 mmol) was added dropwise over 10 minutes, and the resulting mixture was stirred in an ice bath for 20 minutes. The mixture was quenched with saturated sodium bicarbonate solution (10 mL), and the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated by mass to give tert-butyl-2,2-dimethyl-5-(3-(methylsulfonyl) )oxy)propyl)pyrrolidine-1-carboxylate (4.9 g, quantitative yield) as an orange oil. The crude product was used for the next step without further purification. MO-IER t/2 calc. 335.5, found 336.3 (M.-1)k; Holding time: 4.24 min. (Way

РХ 0).

Stage 14: tert-butyl 5-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate to re) o

M 8 -3- M oh

To a solution of 5-(33-methanesulfonyloxypropyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ether (4.9 g, 13.6 mmol) in 1,4-dioxane (70 ml) was added 30 95 aqueous solution of ammonium hydroxide solution (70 ml), and the resulting mixture was heated in a closed container at 60 C for 20 hours. The mixture was concentrated under vacuum and extracted with dichloromethane (3 x 100 ml). The combined organic layers were concentrated to an oil and purified by silica gel chromatography using a 0-1595 dichloromethane-methanol gradient to give tert-butyl-5-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (2 ,14 g, output 61 95 in two stages) in the form of light oil. 1H NMR (500MHz, DMSO) δ 3.66 (a, 1), 2.85 (horn 5, 2H), 2.58-2.48 (t, 2H), 1.85- 1.18 (t, 22H). MO-IER t/2 calc. 256.4, found 257.4 (M--1)x; Holding time: 3.50 min. (The method of RH

AT).

Stage 15: tert-butyl 5-(3-(tert-butoxycarbonylamino)propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

M -- - - k M tert-butyl-5-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (640 mg, 2.496 mmol) was dissolved in dichloromethane (6.4 mL) under a nitrogen atmosphere and triethylamine (1.01 g, 9.981 mmol) was added followed by di-tert-butyl dicarbonate (1.362 g, 6.241 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ether and saturated aqueous ammonium chloride and separated. The aqueous layer was washed twice more with ether, the combined organic phases were dried over sodium sulfate, filtered and concentrated to a light yellow oil, which was purified by silica gel chromatography using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl-5 -III-(tert-butoxycarbonylamino)propyl|-2,2-dimethylpyrrolidine-1-carboxylate (720 mg, 81 95) as a clear oil. MO-IER t/2 calc. 356.26752, found 357.3 (М--1)хк; Holding time: 1.73 min. (Method of RH B).

Stage 16: tert-butyl-5-(3-Ygrett-butoxycarbonyl(methyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate.

Vos

Vos MNVos Vos M

Tert-butyl-5-3-(tert-butoxycarbonylamino)propyl|-2,2-dimethylpyrrolidine-1-carboxylate (720 mg, 2.020 mmol) was dissolved in N,M-dimethylformamide (14.4 mL). Potassium carbonate (837.5 mg, 6.060 mmol) was added, followed by methyl iodide (860.2 mg, 6.060 mmol), and the reaction mixture was allowed to stir at room temperature for 16 hours. Potassium carbonate (1.396 g, 10.10 mmol) was added, followed by methyl iodide (860.2 mg, 6.060 mmol), and the reaction mixture was stirred overnight. Sodium hydride (404 mg, 10.1 mmol) was added and stirred for 6 hours.

Sodium hydride (121 mg, 5.04 mmol) was added, and the reaction mixture was placed in a refrigerator at 4 °C for 3 days. The reaction mixture was warmed to room temperature, methyl iodide (860.2 mg, 6.060 mmol) was added, and the reaction mixture was stirred overnight. at room temperature.

The reaction mixture was diluted with dichloromethane and then washed with water (2 X 40 ml). The organic layer was washed twice with saline and then with saturated aqueous sodium carbonate to bring the reaction mixture to pH 12. After that, the reaction mixture was extracted using dichloromethane (3 x 75 ml). The combined organic fractions were dried over sodium sulfate, filtered and concentrated to give a yellow oil. The residue was purified by silica gel chromatography using a shallow gradient from 10095 dichloromethane to 2095 methanol/dichloromethane to give the product, tert-butyl-5-13-ytt-butoxycarbonyl(methyl)amino|propyl|2,2-dimethylpyrrolidine-i-carboxylate ( 695 mg, 9395) in the form of yellow oil. MO-IER t/2 calc. 370.28317, found 371.5 (M'-1)x; Holding time: 0.83 min. (Method of RH A).

Stage 17: 3-(5,5-dimethylpyrrolidin-2-yl)-M-methylpropan-1-amine (difluoroacetic acid salt).

Vos N

Vos., M. M

M x -- - yat NM M

To a stirred solution of tert-butyl-5-IZ3-(tert-butoxycarbonyl(methyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (695 mg, 1.876 mmol) in methylene chloride (6.95 mL) at 0" trifluoroacetic acid (2.891 mL, 37.52 mmol) was added and the mixture was stirred at room temperature for 5 h.The volatiles were removed under reduced pressure and then

Zo was evaporated from ether 3 times to give 3-(5,5-dimethylpyrrolidin-2-yl)-N-methylpropan-1-amine (difluoroacetic acid salt) (747.3 mg, 100,965). MO-IER t/72 calc. 170.1783, found 171.3 (MA1) k; Holding time: 0.09 min. (Method of RH A).

Stage 18: 2-Chloro-M-((6-fluoro-2-pyridyl)sulfonyl/-6-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-3- carboxamid o o o o o - I Z o-y M OSMO S Ma dOTM MOTO v o E more E

K) EzC 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (1.14 g, 3.03 mmol) and carbonyldiimidazole (590 mg, 3.639 mmol) were combined in tetrahydrofuran (15.3 mL) and stirred for 2 h. At this point b-fluoro-2-pyridinesulfonamide (534 mg, 3.03 mmol) was added, followed by 1,8-diazabicyclo/ 5.4. Fundec-7-ene (907 μl, 6.07 mmol) and the reaction mixture were stirred for another 30 min at room temperature. The reaction was diluted with ethyl acetate and washed with TM citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate and evaporated to give a white solid. The solid was treated with ether, removed under reduced pressure and then dissolved in a minimal amount of hot dichloromethane. The reaction mixture was slowly cooled to room temperature, then in an ice water bath to give a mass of white solid, which was filtered and washed with hexane.The solid was dried under reduced pressure with o holding 2-chloro-M-((b-fluoro-2-pyridyl)sulfonyl|-6-

13-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (1.48 g, 89 95).

MO-ER t/2 calc. 533.05475, found 543.3 (M--1)k; Holding time: 0.72 min. (Method of RH A).

Stage 19: 2-chloro-M-((6-(3-(5,5-dimethylpyrrolidin-2-yl)propyl-methyl-amino)-2- pyridyl|sulfonyl|-6-(3-(2-( 11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (in

J chen B

MI, GO. we are in 0-47 MU s i "MM SI

TT entrance

EZS

2-chloro-M-((6b-fluoro-2-pyridyl) sulfonyl|-6-(3-(2-11 (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide) (1.033 g, 1.876 mmol), 3-(5,5-dimethylpyrrolidin-2-yl)-N-methylpropan-1-amine (difluoroacetic acid salt) (747.3 mg, 1.876 mmol), potassium carbonate (1.556 g, 11.26 mmol ) and dimethyl sulfoxide (5 ml) were added to the vial, closed with a lid and heated to 50 "C for 20 min. The reaction mixture was heated to 65 "C for 90 minutes. The reaction mixture was again cooled to 50 "C and stirred for 32 hours. The reaction mixture was cooled to room temperature and 2-chloro-

M-Kb-fluoro-2-pyridyl)sulfonyl)-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (300 mg, 0.5451 mmol), then reheated to 50°C and stirred overnight. The reaction mixture was cooled to room temperature and poured into water to give a white precipitate. Concentrated hydrochloric acid was added to adjust the H to 4, and then the white solid was filtered off and washed with water and then with hexane The solid was dissolved in dichloromethane, dried (magnesium sulfate), filtered, and concentrated to a white solid. (6-(3-(5,5-dimethylpyrrolidin-2-yl)/propylmethyl-amino|-2-pyridyl|sulfonyl|- 6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1- yl|pyridine-3-carboxamide (350 mg, 27 95) as a white solid. MO-IER t/2 calcd. 683.2268, found 684.5 (Ma-1)w; Retention time: 0 ,63 min. (Method of RH A).

Stage 20: 12,12,19-trimethyl-8-(3-12-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,19 ...

M. 2 M a - M. o-y M M SI z o Hm M M A o R

They combined 2-chloro-M-I((6-(3-(5,5-dimethylpyrrolidin-2-yl/upropylmethylamino |-2- pyridyl|sulfonyl|-6-(3-(2-(11-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-

Co) carboxamide (350 mg, 0.5116 mmol), potassium carbonate (353.5 mg, 2.558 mmol), cesium fluoride (116.6 mg, 28.34 μl, 0.7674 mmol), Z A molecular sieves and dimethyl sulfoxide (7.077 ml) in a flask, purged with nitrogen, closed with a lid, heated to 150 "C and stirred for 25 hours. Cooled to room temperature, then poured into - 150 ml of water. The pH was adjusted to 4 by adding concentrated hydrochloric acid dropwise, obtaining a reddish-brown precipitate which was filtered and washed with water, then with hexane.The solid was dissolved in dichloromethane, dried (magnesium sulfate), filtered and concentrated to a tan solid which was purified by silica gel chromatography using a shallow gradient from 100 95 dichloromethane to 20 95 methanol/dichloromethane, obtaining 12,12,19-trimethyl-8-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9 . 9) (259.5 mg, 78 95). IN NMR (400 MHz, DMSO-46) b 12.62 (5, 1H), 8.22 (a, 9U - 2.8 Hz, 1H), 7.97 (5, 1H), 7.77 (da, U - 8.6, 7.3 Hz, 1H) . 7.1 Hz, 2H), 2.96 (5, ЗН), 2.08, 9 - 7.0

Gu, 2H), 1.69 (5, 2H), 1.54 (y, U - 9.7 Hz, 5H), 1.35 (5, ЗН), 1.23 (5, 7H), 0.98 - 0.95 (t, 2H), 0.89 (Pa ,

In t 5.8, 4.6, 3.0 Gu, 2H). MO-IER t/2 calc. 647.2502, found 648.2 (M--1)f; Holding time: 2.05 min. (Method of RH B).

Example 2: Preparation of (155)-12,12,19-trimethyl-8-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3, 9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(24),5(10),6,68,20,22-hexane-2,2,4-trione (Compound 10 ) its (15K)-12,12,19-trimethyl-8-(3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy)-1 H-

pyrazol-1-yl)-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15|)tetracose-1(24),5(10),6,8,20, 22-hexane-2,2,4-trione (Compound 11) 9 and y 9

Male Zier1 Male Male 0-52 MTM OM - - - 0-5 MTM OM and o-«4 MTM ve Kk -- ko ve k -- ZO Shchi 7 a code

Stage 1: (155)-12,12,19-trimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9, 11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15|)hetracose-1(24),5(10),6,8,20,22-hexane-2,2,4--rione (Compound 10 ) its (15K)-12,12,19-trimethyl-8-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9, 11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)tetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (Compound 11) 7 9 7 oo 7 9 0-47 7M Ohm -- 0-2 MTM m and o-4 MTM m

Shchi Kk A vo Shchi Kk a ZO Shch Kk -i mod Ya

Racemic 12,12,19-trimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,19 ,24-pentaazatetracyclo|18.3.1.05,10.011,15|)tetracose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (compound 9) (221, 5 mg, 0.3420 mmol) to chiral separation by NKR chromatography using SpPigaiRak A5-H (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 15 95 methanol/85 95 carbon dioxide at 10 ml/ min for 8.0 min (injection volume - 500 μl of a 32 mg/ml solution in methanol) with obtaining as the first eluted enantiomer (155)-12,12,19-trimethyl-8-(3-12-11- (trifluoromethyl )cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(24),5(10 ),6,68,20,22-hexane-2,2,4-trione (compound 10) (82.3 mg, 74 95) as a white solid; yin NMR (400 MHz, DMSO-ab) b 12.64 (5, 1H), 8.22 (a, U - 2.68 Hz, 1H), 7.98 (a, 9U - 8.3 Hz, 1H), 7.77 (9 - 7.9 Hz, 1H ), 7.12 (a, 7.2

Hz, TN), 7.04 (5, 1H), 6.82 (a, U - 8.6 Hz, 1H), 6.13 (a, U - 2.68 Hz, 1H), 4.32 (I, U - 7.0 Hz, 2H), 3.60 ( 5, 1H), 2.99 (5, 1H), 2.96 (5, ЗН), 2.08 (Y, 9 - 7.1 Gu, 2Н), 1.96 - 1.84 (t, 1Н), 1.69 (5, ЗН), 1.52 (5 , 6H), 1.35 (5, ZN), 1.02 - 0.83 (t, 5H), MO-IER t/2 calc. 647.2502, found 648.4 (M--1)k; Holding time: 2.06 min. (Method of RH B), apa ah She 5esopa epapioteg (o eishe (15K)-12,12,19-shiteiNuiY!- 8-(3-12-11-(pypiogoteiNu!)susiorgoruCeiyohu)-1H-rugago1-1-yl )-2Ab6-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(24),5(10),6,68,20,22-hexaene-2, 2,4-trione (Compound 11) (81.7 mg, 74 95) az a m/pye 5oiia; IN NMR (400 MHz, DMSO-ab) b 12.64 (5, 1H), 8.22 (y,

U -2.8 Hz, 1H), 7.98 (a, U - 8.3 Hz, 1H), 7.77 (1.9 - 8.0 Hz, 1H), 7.12 (a, U - 7.3 Gu, 1H), 7.03 (5, 1H),

Zo 6.81 (a, 9 - 8.6 Hz, 1H), 6.12 (ai, U - 2.7 Hz, 1H), 4.41 (5, 1H), 4.32 (I, 9 - 7.0 Gu, 2H), 3.59 (5, 1H) . , 1.35 (5, ZN), 1.01 - 0.83 (t, 5H), MO-IER t/2 calc. 647.2502, found 648.4 (Ma-1); Holding time: 2.06 min. (Method of RH B).

Example 3: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18 ,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 12)

o (c) (o) o g Vir 1 bu Vier2 bu Zier Z bo Zeriai, ma" MO"

Gee! at)

J on shk J on pt od - oh ru tet oo nm z o od t uv MN; without (about " M. uva let,

EM Fo Y o-0 Mo in r

Vos

Her time is 9

M lne Zer 11 M u rane Zier 12 Se y: 0-4 toi pivoshsh o-4MM sonia M. 2 SO vk "sec "vd

EzS in y

Stage 1: (E)-(2-oxotetrahydropyran-Z-ylidene)methanolate (sodium salt) o (c; 00-75

Ma"

A 5 L three-neck round-bottom flask was equipped with a mechanical stirrer, a heating hood, a dropping funnel, a 9-Ket temperature sensor/controller, and a nitrogen inlet/outlet. Sodium hydride (59.91 g, 60 95 wt., 1.498 mol) was charged into the vessel under nitrogen, followed by heptane (1.5 L), which gave a gray suspension.

Stirring was started and the temperature in the vessel was recorded at 19 "С. Then ethyl alcohol (3.451 g, 74.91 mmol) was loaded into the vessel, which was added using a syringe, which led to the release of gas. A transparent yellow solution of tetrahydropyran-2 was introduced into an additional funnel -one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 hour, resulting in gas evolution and gradual heating to 45 "С.

The obtained dense white suspension was heated to 65 C for 2 hours. and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was filtered under vacuum through a Buchner funnel with a glass frit (medium porosity) under a stream of nitrogen. The precipitate on the filter was washed by displacement with heptane (2 x 250 ml) and extracted for several minutes. The wet precipitate with a small amount of heptane was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 hours to give a white solid (205 g, 1.36 mol, yield 91,905) as the desired product (E)-(2 -oxotetrahydropyran-Z-ylidene) methanolate (sodium salt).

Stage 2: Z-methylenetetrahydropyran-2-one (c) (c) arable

Ma"

A 5 L three-necked round-bottom flask was equipped with a mechanical stirrer, a heating hood, a dropping funnel, a 9-Ket temperature sensor/controller, and a nitrogen inlet/outlet. The vessel was charged with (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt) (205 g, 1.366 mol) and tetrahydrofuran (1640 mL) under nitrogen to give a white suspension. Stirring was started and the temperature in the vessel was recorded at 19 "C. Then paraformaldehyde (136.6 g, 4.549 mmol) was introduced into the vessel in the form of a solid substance in one portion. The resulting suspension was heated to 63 "C and

The conditions were maintained for 15 hours. When heated, the reaction mixture became slightly gel-like. The white jelly-like mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was partitioned between ethyl acetate (1000 mL), saturated sodium chloride (500 mL), and saturated sodium bicarbonate (500 mL) in a separatory funnel.

The organic phase was removed and the remaining aqueous layer was extracted with ethyl acetate (5 x 300 ml). The combined organic compounds were dried over sodium sulfate (500 g) and then vacuum filtered through a Buchner funnel with a 20 mm celite-lined glass frit. The precipitate on the filter was washed by displacement with ethyl acetate (250 ml). The pure filtrate was concentrated under reduced pressure to give a clear pale yellow oil (135 g) as the expected crude product. The material was purified by flash chromatography on a column with silica gel (liquid loading), eluting with a gradient from 100 95 hexanes to 60 95 ethyl acetate in hexane for 1 h, collecting fractions of 450 ml. The product was detected by TLC analysis on silica gel, eluting with a mixture of hexanes/ethyl acetate 3:1, and visualized under UV. The product fractions were combined and concentrated under reduced pressure to obtain a clear colorless oil (132 g, 1.18 mol, yield 72 95, containing 16 wt. 965 residual ethyl acetate according to

NMR) as the desired product, 3-methylenetetrahydropyran-2-one. IN NMR (400 MHz, DMSO-ab) b 6.18 (d, U - 1.9 Hz, 1H), 5.60 (ad, y - 1.9 Hz, 1H), 4.40 - 4.26 (t, 2H), 2.61 (av, o - 7.0, 6.3, 2.0 Hu, 2H), 1.90 - 1.75 (t, 2H).

Stage 3: 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one o (c)

WITH -

Mo

A 5000 ml three-neck round-bottom flask was equipped with a mechanical stirrer, a cooling bath, which is used as a secondary protective jacket, a temperature sensor in

Cat, drip funnel and nitrogen inlet/outlet. 2-nitropropane (104.9 g, 1.177 mol) was charged into the vessel under a nitrogen atmosphere. Stirring was started and the temperature in the vessel was recorded at 19°C. Then 1,8-diazabicyclo/5.4.F)undec-7-ene (22.41 g, 147.2 mmol) was added to the vessel in pure form in one portion , resulting in a clear light yellow solution. No exotherm was observed. A solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 mL) was added dropwise over 1 h to a dropping funnel. , which led to a transparent light yellow solution and a gradual exothermic effect up to 24 C.

The reaction mixture was continued to be stirred at room temperature for 3.5 h and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (1000 mL) and partitioned with 500 mL of a 3:2 1 molar citric acid/saturated sodium chloride solution. The newly formed organic phase was a clear pale blue solution and the aqueous phase was a slightly cloudy very pale blue solution. The organic layer was removed and the residual aqueous layer was extracted with dichloromethane (300 mL). The combined organic compounds were washed with brine (300 mL), dried over sodium sulfate (250 g) and then filtered through a Buchner funnel with a glass frit. The filtrate was concentrated under reduced pressure to a volume of approximately 200 ml. The clear, pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 mL) and the opaque solution was concentrated under reduced pressure to a volume of approximately 200 mL to give a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 ml) and concentrated under reduced pressure to a volume of approximately 250 ml. The resulting suspension was left overnight at room temperature (about 12 hours). The solid was collected by vacuum filtration in a Buchner funnel with a glass frit, the precipitate on the filter was washed with cold methyl tert-butyl ether (2 x 150 mL) and then extracted for 30 min. The material was further dried in a vacuum oven at 45 "C for 5 hours to obtain (160 g, 0.795 mol, yield 81 95) a white solid as the desired product, 3-(2-methyl-2-nitropropyl)tetrahydropyran-2-one TN NMR (400 MHz, DMSOSO-ab) b 4.34 (dad9, 9 - 11.1, 9.3, 4.3 Hu, 1H), 4.20 (a, 9 - 11.1, 5.1 Hz, 1H), 2.75 - 2.62 (t, 1H) . - 12.8, 11.5, 8.1, 6.6 Hz, 1H).

Stage 4: 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one and)

Ge; NM about

MO, Z on

A three-necked 1000 mL round-bottom flask was equipped with a Teflon stirring rod, a heating cap, a -)-Ket temperature sensor/controller, and rubber membranes. The vessel was charged with 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (25 g, 124.2 mmol) and ethyl alcohol (375 mL), which gave a white suspension. Stirring was started and the suspension was heated to 40 °C for 10 minutes, which gave a clear, colorless solution.

Then the vessel was equipped with a gas dispersion tube, and the solution was degassed with nitrogen for 15 min. Raney nickel (8.019 g, 50 95 w/w, 68.31 mmol) was then loaded into the vessel, and the vessel was then equipped with baffles. The vessel was evacuated and placed in a hydrogen atmosphere. The process was repeated for three cycles. Then the vessel was placed in a hydrogen atmosphere with 1 atmosphere and the reaction mixture was gradually heated to 60 "C. The reaction mixture was continued to be stirred at 60 "C for 24 hours. After cooling to room temperature, the vessel was equipped with a gas dispersion tube and the reaction mixture was degassed with nitrogen for 15 min. The mixture was filtered under vacuum through a Buchner funnel with a glass frit with a 20 mm celite layer. The filter cake was washed by displacement with ethanol (2 x 100 mL) and extracted until it was slightly wet with ethyl alcohol, then wetted with water, and the spent nickel Raney catalyst was drained off under water. The clear pale amber filtrate was concentrated under reduced pressure to a clear, viscous light amber oil. The oil was diluted with methyl tert-butyl ether (1500 mL) and the opaque solution was concentrated under reduced pressure to a volume of approximately 150 mL to give a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 ml) and concentrated under reduced pressure to a volume of approximately 150 ml. The resulting suspension was left overnight at room temperature (about 12 hours). The solid was collected by vacuum filtration on a Buchner funnel with a glass frit, the precipitate on the filter was washed with cold methyl tert-butyl ether (2 x 50 mL), and then extracted for 30 min. The material was additionally dried in a vacuum oven at 45 "С during

From hours to obtain a white solid (19 g, 0.111 mol, yield 89 95) as the product, 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one. TN NMR (400 MHz, DMSO-ab) b 7.63 (5, 1H), 3.38 (9 - 6.5 Hz, 2H), 2.37 (da, 9 - 9.8, 8.5, 4.4 Hz, 1H), 2.02 (da, U - 12.3, 8.6 Hz, 1H), 1.72 (yes, 9 - 9.6, 7.5, 4.4 Hz, 1H), 1.52 - 1.32 (t, ЗН), 1.28 - 1.03 (t, 7H).

Stage 5: 3-(5,5-dimethylpyrrolidin-3-yl)upropan-1-ol nm o nm ----

Z on AH on

A 5 L three-necked round-bottom flask was equipped with a mechanical stirrer, a heating hood, a dropping funnel, a 9-Ket temperature sensor/controller, and a nitrogen inlet/outlet. Lithium aluminum hydride granules (19.39 g, 510.9 mmol) were loaded into the vessel under a nitrogen atmosphere. Then tetrahydrofuran (500 ml, 20 ml/g) was loaded into the vessel. Stirring was started and the temperature in the vessel was recorded at 20 s.

The mixture was allowed to stir at room temperature for 0.5 h to allow the granules to dissolve. The reactor temperature of the obtained gray suspension was 24 "C. A solution of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (25 g, 146.0 mmol) in tetrahydrofuran (500 ml) was added dropwise to the dropping funnel a transparent pale yellow solution was added for 90 min. A little heating was required to achieve homogeneity. After the addition was completed, the temperature of the reservoir of the obtained grayish suspension was fixed at 24 °C. The mixture was then heated to a boiler temperature of 65 °C and the conditions were maintained for 72 hours. Analysis of the reaction mixture at this point showed that some residual starting material still remained and no change in product formation. The reaction was subsequently stopped at this stage. The heating jacket was removed and the vessel was fitted with a cooling bath.The suspension was cooled to 0 C using a crushed ice/water cooling bath and then quenched by the very slow dropwise addition of water (19.93 mL) followed by 15 wt 95 hydroxide solution sodium (19.93 ml) and then again water (59.79 ml). The temperature of the obtained white suspension was 5 "C.

The cooling bath was removed, and the vessel was again equipped with a heating jacket. The suspension was heated to 60 "С and kept for 30 min. The warm suspension was filtered under vacuum through a Buchner funnel with a glass frit with a layer of Celite of 20 mm. Then the sediment on the filter was washed by displacement with tetrahydrofuran at 60 "С (2 x 250 ml) and then extracted during 30 min. The clear filtrate was concentrated under reduced pressure to give (23.5 g, 0.149 mol, yield 9995) a clear light yellow viscous oil as the desired product, 3-(5,5-dimethylpyrrolidin-3-yl/upropan-1- 1H NMR (400 MHz, DMSOO-ab) b 3.37 (а, 9 - 8.3, 6.4 Hz, ЗН), 2.95 (da, У - 10.6, 7.6 Hz, 1Н), 2.40 (da, 9 - 10.7, 7.7 Hz, 1H), 2.04 (a, U - 16.1, 8.1 Hz, 1H), 1.69 (aa, U - 12.2, 8.2 Hu, 1H), 1.50 - 1.24 (t, 5H), 1.11 - 0.94 (t, 7H) .

Stage 6: tert-butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

NM VosM ---kh

AH on 2 on

A three-necked round-bottom flask with a volume of 1 L was equipped with a mechanical stirrer, a cooling bath, a dropping funnel, a .)-Ket temperature sensor, and a nitrogen inlet/outlet. 3-(5,5-dimethylpyrrolidin-3-yl)upropan-1-ol was loaded into the vessel under a nitrogen atmosphere

(15 g, 95.39 mmol) and dichloromethane (225 mL, 15 mL/g), which gave a clear light yellow solution.

Stirring was started and the temperature in the vessel was recorded at 19 °C. Crushed ice/water was loaded into the cooling bath, and the temperature in the container was lowered to 0 °C. The dropping funnel was charged with triethylamine (12.55 g, 124.0 mmol), which was then added dropwise in its pure form over 5 minutes. No exotherm was observed. Then di-tert-butyl dicarbonate (22.89 g, 104.9 mmol) dissolved in dichloromethane (225 mL) was charged into the dropping funnel. Then, a transparent, pale yellow solution was added dropwise for 30 minutes, which led to a gentle release of gas. No exotherm was observed. The cooling bath was removed and the resulting clear light yellow solution was allowed to warm to room temperature and stirring was continued at room temperature for 3 hours.

The reaction mixture was transferred to a separatory funnel and separated with water (75 ml). The organic layer was removed and washed with brine (75 mL), dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to give (30 g) a clear light yellow oil as the desired crude product. The material was purified by flash chromatography on a silica gel column (liquid loading with dichloromethane), eluting with a gradient from 10095 dichloromethane to 1095 methyl alcohol in dichloromethane over 60 minutes, collecting fractions of 50 ml. Fractions of the desired product were combined and concentrated under reduced pressure to obtain tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (22 g, 0.0855 mol, yield 90 95) as a clear pale yellow viscous oil. "IN NMR (400 MHz, OM5O-ab6) b 4.38 (9, U - 5.2, 1.4 Hz, 1H), 3.54 (a, U - 10.3, 6.7 Hz, 1H), 3.38 (19, U - 6.6, 3.5 Hz , 2H), 2.76 (d, U - 10.3 Hz, 1H), 2.07 (Id, 9 - 11.6, 5.7 Hz, 1H), 1.87 (ada, 9 - 16.7, 12.1, 6.0 Hz, 1H), 1.37 (da In - 14.2, 10.4 Hz, 17H), 1.24 (5,

ZN).

Stage 7: tert-butyl 2,2-dimethyl-4-(3-methylsulfonyl oxypropyl)pyrrolidine-1-carboxylate

Tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (50.5 g, 196.22 mmol) and triethylamine (39.711 g, 54.698 mL, 392.44 mmol) were dissolved in dichloromethane ( 500 ml) and the resulting solution was cooled in an ice water bath for 30 min. Mesyl chloride (24.725 g, 16.706 mL, 215.84 mmol) was added dropwise over 30 minutes, followed by an ice bath

Z was removed and the mixture was stirred at room temperature for one hour. Then the reaction was quenched with saturated sodium bicarbonate solution (200 ml). The phases were separated and the organic phase was extracted with saturated sodium bicarbonate (200 mL) and water (2 x 100 mL). The aqueous phases were discarded, and the organic phase was dried over sodium sulfate, filtered and concentrated in oil to obtain tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (64.2 g, 93 95) in the form of a pale yellow oil. MO-IER ip/2 calc. 335.1766, found 336.4 (М-А1)k; Holding time: 5.54 min. (Method РХ 0).

Stage 8: tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (o) mode model (o);

Tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-i-carboxylate (64.2 g, 191.38 mmol) was dissolved in dioxane (650 mL), then ammonium hydroxide (650 mL) was added and the resulting mixture was heated to 45 "C for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature. The solution was diluted with 1 M sodium hydroxide (200 ml), and then extracted with diethyl ether (3 x 650 ml). The aqueous phase was discarded, and The combined organic phases were extracted with water (2 x 200 mL). The aqueous phases were discarded, and the organic phase was dried over sodium sulfate, filtered and concentrated by mass to give tert-butyl 4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1- carboxylate (48.9 g, 95 95) in the form of a pale yellow oil. MO-

IER t/2 calc. 256.2151, found 257.3 (M--1)xk; Holding time: 3.70 min. (The method of RH O).

Stage 9: tert-butyl 2,2-dimethyl-4-3-Kb-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate

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To tert-butyl-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (8.91 g, 34.8 mmol) and b-fluoropyridine-2-sulfonamide (6.13 g, 34.8 mmol) in dimethylsulfoxide (75 mL) was added potassium carbonate (4.91 g, 35.5 mmol) and the mixture was stirred at 100 °C for 12 h, then allowed to cool to ambient temperature and stirred for an additional 4 h (a total of 16 The reaction mixture was slowly poured into hydrochloric acid (35 mL of 1 M, 35.00 mmol) in water (200 mL) (some foaming) and diluted with ethyl acetate (250 mL). The organic phase was separated and washed with 100 mL of brine. phase was dried over magnesium sulfate, filtered through celite, and concentrated in vacuo to give a dark yellow oil. The crude product was purified by silica gel chromatography, eluting with 0 95-100 95 ethyl acetate in hexane. Both pure (9.0 g) and impure were collected (Z d) factions.

Contaminated fractions were purified by chromatography on silica gel, eluting with 0-100 95 ethyl acetate in hexane, obtaining in general tert-butyl-2,2-dimethyl-4-IZ-K(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine- 1-carboxylate (10.0 g, 69 95). IN NMR (400 MHz, DMOO-ab) b 7.52 (ad, 9 - 8.5, 7.2 Hz, 1H), 7.07 (5, 2H), 6.95 (ai, 9 - 7.2, 0.7 Hz, 2H), 6.61 (a, U - 8.5 Hz, 1H), 3.55 (d, U - 9.1 Hu, 1H), 3.32 - 3.24 (t, 2H), 2.79 (d, U 10.0 Hz, 1H), 2.13 (a, U - 16.1 Hu, 1H ), 1.96 - 1.82 (t, 1H), 1.51 (4, 9 - 18.0, 9.3 Hz, 2H), 1.37 (yes, 9 - 12.9, 10.6 Hz, 15H), 1.24 (5, ЗН). MO-IER t/7 calc. 412.21442, found 413.1 (M'-1)k; Holding time: 2.34 min. (Method РХ 0).

Stage 10: tert-butyl 4-(3-C(6-Ce-chloro-6-I3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

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M os. what

Part A: To 2-chloro-6-I3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (11.4 g, 30.34 mmol) in tetrahydrofuran (150 mL) was slowly added carbonyldiimidazole (5.9 g, 36 mmol). The mixture was stirred at ambient temperature for 1 h. Additional carbonyldiimidazole (0.5 g, 3 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 1 hours (only 2 hours).

Part B: To the activated ester obtained in part A was added tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (10.0 g , 24.24 mmol) in tetrahydrofuran (50 mL), then 1,8-diazabicyclo|5.4.FOundec-7-ene (7.5 mL, 50 mmol) and the mixture was stirred at ambient temperature for 16 hours. To

Citric acid (25.1 g, 130.6 mmol) in water (200 mL) was slowly added to the reaction mixture and acidified to pH - 3. The mixture became cloudy, but no precipitate was formed. The mixture was extracted with ethyl acetate (400 mL) and the organic phase was washed with brine, dried over magnesium sulfate, filtered through celite, and concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with 0-80 90 ethyl acetate/hexanes to obtain tert-butyl 4-I3-C(6-C2-chloro-6-(3-(2-(11-(trifluoromethyl)cyclopropyl) as a foam) |ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (13.82 g, 74,965) TN NMR (400 MHz ,

DMSO-ab) b 12.79 (5, 1H), 8.40 (I, U - 2.7 Hz, 1H), 8.11 (a, U - 8.4 Hz, 1H), 7.71 (a, 9 - 8.3 Hz, 1H), 7.62 ( aa, 0) - 8.5, 7.2 Hz, 1H), 7.21 (a, 9 - 5.68 Gu, 1H), 7.17 (y, U - 7.1 Hz, 1H), 6.74 (a, U - 8.5 Hz, 1H), 6.19 (, U - 2.3 Hz, 1H), 4.34 (I, 9 - 7.1 Hz, 2H), 3.50 (4, U - 18.3, 9.0 Hz, 1H), 3.23 (a, 9 - 6.7 Gu, 2H), 2.80 - 2.69 (t, 1H), 2.09 (I, U - 7.1 Hz, 2H), 1.79 (19, U - 12.4, 6.1 Hz, 1H), 1.52 (a, U - 15.4, 8.0

Hu, 2H), 1.36 (y, U - 11.4 Hu, TON), 1.33 - 1.25 (t, 5H), 1.17 (5, 2H), 0.99 - 0.92 (t, 2H), 0.89 (y, 9 - 5.0 Hz , 2H). MO-IER t/2 calc. 769.2636, found 770.1 (Ma-1)-4; Holding time: 3.48 min. (Method РХ 0).

Stage 11: 2-chloro(M)-I((6-3-(5,5-dimethylpyrrolidin-3-yl/upropylamino|-2-pyridyl|sulfonyl|/-6-

IZ-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt)

ooo

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M

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To tert-butyl-4-I3-C(6-C2-chloro-6-I(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl| -2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (13.8 g, 17.92 mmol) in dichloromethane (75 ml) was added hydrochloric acid (15 ml 4 M, 60.00 mmol) and the mixture stirred at ambient temperature for 16 hours.

The solvent was removed in vacuo, and the residue was diluted with 100 mL of ethyl acetate. The solvent was removed in vacuo and repeated with an additional 100 mL of ethyl acetate to give a foam, 2-chloro-(1M)-I(6-I(3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-pyridyl| sulfonyl/|-6-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt)) (13.5 g, 101 95). IN NMR ( 400 MHz, DMSO-ab) b 12.83 (5, 1H), 9.06 (5, 1H), 8.92 (5, 1H), 8.42 (j, 9 - 2.8 Hz, 1H), 8.11 (a, 9. - 8.4 Gu , 1H), 7.72 (a, U - 8.4 Hz, 1H), 7.63 (aa, U - 8.5, 7.2 Hz, 1H), 7.29 (5, 1H), 7.18 (aa, U - 7.2, 0.7 Hz, 1H) . t, 1H), 3.24 (p, U - 6.7 Hz, 2H), 2.80 (NK, U - 11.68, 6.7 Hz, 1H), 2.35 (d, U - 7.68, 7.3 Hz, 1H), 2.09 (Y, U - 7.1 Gu, 2H), 1.91 (yes, 9 - 12.8, 7.6 Hz, 1H), 1.58 - 1.43 (t,

ЗН), 1.42 - 1.31 (t, 5Н), 1.24 (5, ЗН), 1.01 - 0.93 (т, 2Н), 0.90 (aa, U - 7.9, 3.2 Hz, 2Н). MO-IER t/7 calc. 669.2112, found 670.0 (M--1) k; Holding time: 2.26 min. (Method РХ 0).

Stage 12: 12,12-dimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18, 23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 12) o o o o 9 y: m"? y: Ж m"? ех pMore than ov 0-7 /y

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To 2-chloro-M-I(6-I3-(5,5-dimethylpyrrolidin-3-yl)upropylamino|-2-pyridyl|sulfonyl|-6-I(3-(2-11- (trifluoromethyl)cyclopropyl| Ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (12.9 g, 17.36 mmol) in MMP (120 ml) was added potassium carbonate (9.64 g, 69.8 mmol), and then cesium fluoride (2.69 g, 17.7 mmol), and the suspension was stirred at 150 "C for 16 hours.

The reaction mixture was then allowed to cool to ambient temperature. The mixture was diluted with water (100 mL) and poured into water (400 mL), and the mixture was slowly acidified with hydrochloric acid (27.0 mL 6 M, 162.0 mmol). The precipitate was collected using a medium frit and washed three times with 50 ml of water. The solid was air-dried for 1 h and then dissolved in ethyl acetate (400 mL). The organic phase was concentrated in vacuo and crude

The product was purified by chromatography on silica gel, eluting with a mixture of 000-100 95 ethyl acetate/hexanes. 6.3 g of pure product and 6 g of impure fractions were collected. Fractions with impurities were purified by chromatography on silica gel, eluting with a mixture of 0-5 905 methanol/dichloromethane, which ensured a good separation of the product from impurities. Fractions of the pure product were combined to give 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 12) ( 7.4 g, 67 95). NMR (400 MHz, DMSO-ab) b 12.52 (5, 1H), 8.22 (a,

U -2.6 Hu, 1H), 7.62 (a, U - 8.2 Hu, 1H), 7.58 (da, 9 - 8.5, 7.2 Hu, 1H), 7.05 (y, 9 - 7.0 Hu, 1H), 7.00 (5, 1H), 6.92 (y, 9 - 8.2 Hz, 1H), 6.71 (0.9 -8.2 Hz, 1H), 6.11 (a, U - 2.8 Hz, 1H), 4.31 (U. - 7.0 Hz, 2H), 4.02 - 3.81 (t, 1H), 3.15 (1, U - 10.1, 3.8 Hz, 1H), 2.95 (a, U 2 13.7 Hu, 1H), 2.78 - 2.61 (t, 1H), 2.15 (da, U - 5.7, 2.9 Hz, 1H), 2.07 (a, U - 6.4 Gu, 2H), 1.92 - 1.82 (t, 1H), 1.81 - 1.69 (t, 1H), 1.64 - 1.53 (t, 6H), 1.51 (5 , ZN), 1.36 - 1.23 (t, 1H), 0.99 - 0.93 (t, 2H), 0.90 (j, U - 10.68 Gu, 2H). MO-IER t/72 calc. 633.2345, found 634.2 (M'-1)k; Holding time: 2.23 min. (Method of RH E).

Example 4: Preparation of (14K)-12,12-dimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9 . )-12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23 - pentaazatetracyclo(17.3.1.111,14.05,10)|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 14) o 9 o 9 o 9 ts same d- driver's sun Чи d- d There are many ts 7 d- Z

Stage 1: (14K)-12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9, 11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 13) and (145 )-12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23 - pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 14) 7 oo ooo 7 to 0- 0 M M Ma 0-0 M M What - I o-s M M Ma what Kk - With in still 7 - 3 There are still days ZhK - modoya

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (7.4 g) was dissolved in 150 ml acetonitrile and subjected to chiral purification

NKRKH The sample was separated by chiral NCR chromatography using SpPigaiYRak AVB-N (column 250 X 21.2 mm, particle size 5 μm) with 25 95 acetonitrile:methanol (90:10))/75 Fo carbon dioxide as the mobile phase at 70 ml/ min. with obtaining the first eluted enantiomer (14K)-12,12-dimethyl-8-(3-12-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3, 9,11,18,23-pentaazatetracyclo!|17,3,1,111,14,05,10|htetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione ( Compound 13 ) (2.91 g, 53 95); 1L NMR (400 MHz, DMSOSO-abb) b 12.51 (5, 1H), 8.21 (a, 9 - 2.7 Hz, 1H), 7.82 (a, U - 8.2 Hz, 1H), 7.58 (1, U - 7.8 Hz, 1H), 7.05 (a, U - 7.0 Hz, 1H), 6.99 (a, y - 5.8 Hz, 1H), 6.92 (j, U - 8.2 Hz, 1H), 6.71 (a, 9 - 8.5 Hz, 1H), 6.11 (a, U - 2.7 Hz, 1H), 4.31 (i, 9 - 7.0 Gu, 2H), 3.93 (5, 1H), 3.16 (5, 1H), 2.95 (y, U - 12.7 Hz, 1H), 2.80 - 2.64 (t, 1H), 2.10 (5, 1H), 2.08 (I, U - 7.1 Gu, 2H), 1.86 (ai, 9 - 11.5 . , 2H), 0.89 (5, 2H); MO-IER t/2 calc. 633.2345, found 634.3 (M-a-1)g; Retention time: 2.19 min.; and the second eluted enantiomer, (145)-

Zo 12,12-dimethyl-8-(3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracycloyl17 ,3,1,111,14,05,10|tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (Compound 14) (3.0 g, 54 95) NMR (400 MHz, DMSO-ab) b 12.52 (5, 1H), 8.22 (y, 9 - 2.8 Hz, 1H), 7.82 (y, U - 8.2 Hz, 1H), 7.58 (ai, 9 - 8.5, 7.1 Hz, 1H), 7.05 (a, U - 7.2 Hz, 1H), 6.99 (5, 1H), 6.92 (94.9 - 8.2 Hz, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.11 (a, U - 2.8 Hz, 1H), 4.31 (I, U - 7.0 Hz, 2H), 3.92 (y, 9 - 12.6 Hz, 1H), 3.15 (5, 1H), 2.95 (y, U - 13.2 Hz . 6Н), 1.51 (5, ЗН), 1.31 (d, U - 11.9 Hz, 1Н), 1.00 - 0.92 (t, 2Н), 0.90 (а, У - 10.4 Hz, 2Н). MO-IER t/: calc. 633.2345, found 634.1 (Ma1)j; Holding time: 2.2 min. (Method of RH B).

Example 5: Preparation of 12,12-dimethyl-8-(3-C1-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18,23-pentaazatetracyclo |1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 15)

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Stage 1: tert-butyl 3-(P1-(trifluoromethyl)cyclopropyl|methoxy|pyrazole-1-carboxylate o)one o m. Z

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5000 mL three-neck round-bottom flask equipped with mechanical stirrer, heating cap, .)-Ket temperature sensor/controller, dropping funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. Tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (70 g, 0.3800 mol) and tetrahydrofuran (840 mL, 12 mL/g) were charged into the vessel under a nitrogen atmosphere, which gave a clear pale yellow solution . Stirring was started and the temperature in the vessel was recorded at 19 °C. Then it was loaded into the vessel

N-trifluoromethyl)cyclopropyl|methanol (58.56 g, 0.4180 mol) added neat in one portion, followed by triphenylphosphine (109.6 g, 0.4180 mol) added as a solid in one portion. The resulting clear, pale yellow solution was then treated with diisopropyl azodicarboxylate (clear reddish-orange liquid) (82.3 mL, 0.4180 mol) added dropwise over 1 h, resulting in a gradual exothermic effect to 40 "C and a clear light -yellow solution. Then the reaction mixture was heated to a temperature of 50 "C and the conditions were maintained for 2 hours, when the analysis

LC/MS showed complete consumption of the starting material. The clear amber reaction mixture was concentrated under reduced pressure, and the resulting clear dark amber oil was suspended in toluene (560 mL) and stirred at room temperature for 1 h, during which a precipitate (MM triphenylphosphine - 278.28) formed. The thick suspension was filtered through a Buchner funnel with a glass frit and the precipitate on the filter was washed with toluene (150 mL) and then extracted for 30 min. The pure amber filtrate was concentrated under reduced pressure to obtain a clear amber oil. The material was purified by flash chromatography on a silica gel column (solid load adsorbed on celite), eluting with a gradient from 100 95 hexanes to 20 95 ethyl acetate in hexane, collecting fractions of 450 ml. The product was eluted with about 5 95 ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure to give a clear pale yellow oil as the desired product, tert-butyl-3-((1-(trifluoromethyl)cyclopropyl|methoxy|pyrazole-1-carboxylate (81 g, 0.264 mol . , 9H),

Zo 1.07 (ar, y - 4.9, 1.3 Hz, 4H). MO-IER t/2 calc. 306.11914, found 307.0 (M--1)f; Holding time: 1.75 min. (Method of RH B).

Stage 2: 3-(1-«(trifluoromethyl)cyclopropyl|methoxy|-1 H-pyrazole (c) m.

EE GE

A three-necked 5000 mL round-bottom flask was equipped with a mechanical stirrer, a heating hood, a U-Cat temperature sensor, a water reflux condenser, a dropping funnel, and a nitrogen inlet/outlet. Tert-butyl-3-(1-(trifluoromethyl)cyclopropyl|petoxy|pyrazole-1-carboxylate (80 g, 0.2612 mol), dichloromethane (320 ml, 4 ml/g) and methyl alcohol were charged into the vessel under a nitrogen atmosphere (320 ml, 4 ml/g), which gave a clear, pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 19 °C.

A dropping funnel was charged with 4 M hydrochloric acid in 1,4-dioxane (195.9 mL, 0.7836 mol), which was then added dropwise over 1 h, leading to a gradual exotherm to 30 °C. The resulting transparent pale yellow the solution was heated to a temperature of 45 °C and the conditions were maintained for 1 h, when analysis by LC/MS showed the completion of the reaction.

The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved in tert-butyl methyl ether (640 ml), then transferred to a separatory funnel and separated with 2 M sodium hydroxide solution (391.8 ml, 0.7836 mol).

The organic layer was removed, and the remaining aqueous layer was extracted with methyl tert-butyl ether (2 x 200 ml). The combined organic compounds were washed with brine (500 mL), dried over sodium sulfate (300 g) and then filtered through a Buchner funnel with a glass frit. The clear pale yellow filtrate was concentrated under reduced pressure to give a clear light yellow oil which solidified on standing to give a white solid (49.5 g, 0.240 mol, 92595) as the desired product, 3-(1-(trifluoromethyl) cyclopropyl|methoxy|-1H-pyrazole 1H NMR (400 MHz, DMSO-ab) b 11.90 (5, 1H), 7.51 (8.9 - 2.4 Hz, 1H), 5.67 (0, U - 2.4 Hz, 1H) , 4.19 (5, 2H), 1.09 - 0.97 (t, 4H). MO-IER t/27 calculated 206.0667, found 207.0 (M--1) k; Retention time: 1.08 min ( Method РХ B).

Stage C: tert-butyl 2-chloro-6-I3-(P1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridine-3-carboxylate) those

E E drink

EE

A three-necked 5000 mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary protective shell, a U-Cat temperature sensor, a water reflux condenser, a dropping funnel, and a nitrogen inlet/outlet. 3-|((1-"trifluoromethyl)cyclopropyl|methoxy |-

1H-pyrazole (45 g, 0.2183 mol) and M,M-dimethylformamide (540 mL, 12 mL/g) were added to give a clear pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 17 °C.

Then tert-butyl-2,6-dichloropyridine-3-carboxylate (54.16 g, 0.2183 mol) was loaded into the vessel, which was added as a solid in one portion. Then, the resulting transparent pale yellow solution was treated with potassium carbonate (39.22 g, 0.2838 mol) as a solid in one portion followed by the addition of 1,4-diazabicyclo(2,2,2)|octane (3.67 g, 0.03274 mol) as a solid in one portion. The resulting pale yellow suspension was left under stirring at room temperature for 24 hours. The reaction mixture was cooled to 10 C using a crushed ice/water cooling bath. Water (540 mL) was added dropwise to the dropping funnel over 45 min, resulting in the formation of a thick suspension and an exothermic reaction to 15 "C. The resulting suspension was continued to stir at 15 "C for 30 min and then filtered through a Buchner funnel with a glass frit . The sediment on the filter was washed by displacement with water (2 x 500 ml), and then drawn into a Buchner funnel for 2 hours. The material was then allowed to air dry overnight to give (73 g, 0.175 mol, 80 95) a white granular solid, tert-butyl 2-chloro-6-I3-(P1-(trifluoromethyl)cyclopropyl|methoxy|pyrazole-1 -yl|pyridine-3-carboxylate MO-IER t/2 calcd 417.1067, found 418.1 (M--1)g Retention time: 0.85 min (RC Method A).

Stage 4: 2-chloro-6-I3-(P1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridine-3-carboxylic acid c) Х (Ф) 9-0 M' cc --t- 9 -0 M ss I in

Ee Ee

1000 mL three-neck round-bottom flask equipped with mechanical stirrer, heating cap, 9U-Ket temperature sensor/controller, dropping funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. Tert-butyl-2-chloro-6-I3-(1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridine-3-carboxylate (70 g, 0.1675 mol) and 2 -propanol (350 mL), which gave an off-white suspension. Stirring was started and the temperature in the vessel was recorded at 1970. Aqueous 6 M hydrochloric acid (139.6 mL, 0.8375 mol) was charged into the dropping funnel, which was added dropwise over 10 minutes, which led to exothermy up to 30 "C. Then the obtained suspension was heated with a reflux condenser (temperature of the container - 82 "C). When heated, the suspension turned into a transparent pale yellow solution (temperature of the container at this moment - 75 "C). After stirring under reflux for -30 min, a solid precipitate began to form. The suspension was continued to stir under reflux for an additional 30 min, after which water (210 mL) was added dropwise over 15 min. Heating was then stopped and the suspension was continued for stir and let it slowly cool to room temperature. The material was collected by vacuum filtration in a Buchner funnel with a glass frit, and the sediment on the filter was washed by displacement of 1:1 water/2-propanol (100 ml), then with water (2 x 100 ml), and then drawn into a Buchner funnel for 30 minutes. The material was further dried in a vacuum oven at 45 "C for 24 hours to obtain 2-chloro-6-I3-(1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridin-

C-carboxylic acid (56 g, 0.155 mol, 92 95) as a white solid. TN NMR (400

MHz, DMSO-46) b 13.64 (5, 1H), 8.44 (a, U - 2.9 Hz, 1H), 8.41 (a, U - 8.4 Gu, 1H), 7.74 (y, U - 8.4 Hz, 1H), 6.24 (0.9 - 2.9 Hu, 1H), 4.41 (5, 2H), 1.16 - 1.07 (t, 4H). MO-IER t/: calc. 361.0441, found 362.1 (M--1)k; Holding time: 0.66 min. (Method of RH A).

Stage 5: tert-butyl 4-I3-(6-C(2-chloro-6-I3-(1-trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate 9 ooo -Z x//

It is about 4 MM of that ro m | In he Y MN from -Й MN plait ShK ---0263 Z - to «y

Bos Bos 2-Chloro-6-3-(1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (260 mg, 0.6973 mmol) and carbonyldiimidazole (113.1 mg, 0 .6973 mmol) were combined in

From tetrahydrofuran (3.783 ml) and stirred for 1 h at 45 "C. Tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate ( 287.7 mg, 0.6973 mmol), and then 1,8-diazabicyclo[(4.0)undec-7-ene (212.4 mg, 208.6 μl, 1.395 mmol), and the reaction mixture was heated at 45 °C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, evaporated, then purified by chromatography on silica gel (24-gram column) using a gradient from 100 95 hexanes to 70 95 ethyl acetate in hexane to obtain tert-butyl-4-I3- ((6-Ce-chloro-6-(3-((/1- (trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2 -dimethylpyrrolidine-1-carboxylate (232 mg, 44 95). NMR (400 MHz,

DdMSO-ab) b 12.78 (5, 1H), 8.41 (j, 9 - 2.4 Hz, 1H), 8.11 (a, 9 - 8.3 Hz, 1H), 7.72 (a, Y - 8.3 Hz, 1H), 7.62 ( yes, 9 - 8.4, 7.3 Hz, 1H), 7.21 (5, 1H), 7.17 (a, 9U - 7.1 Hz, 1H), 6.74 (a, U - 8.5 Hz, 1H), 6.23 (5, 1H), 4.39 (5, 2H), 3.58 - 3.46 (t, 1H), 3.24 (5, 2H), 2.74 (I, U - 10.5 Hz, 1H), 2.02 (5, 1H), 1.79 (4, 9 2 12.2, 6.4 Hz, 1H), 1.50 (give, u - 21.4, 10.3, 6.2 Hz, 2H), 1.36 (y, 9 - 11.7 Hz, 9H), 1.30 (a, U - 13.68

Hz, 6Н), 1.17 (5, ЗН), 1.11 (5, 2Н), 1.09 (5, 2Н). MO-IER t/2 calc. 755.248, found 756.5 (Ma1)xk; Holding time: 2.31 min. (The method of RH is).

Stage 6: 12,12-dimethyl-8-(3-111-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo| 1 7.3.1.111,14.05,10|htetracose-1(23),5(10)6,8,19,21-hexane-2,2,4-trione (Compound 15) because of Me ischvya and 7th

Ezs - MN «y

Vos

Part A: tert-butyl-4-I3-(6-Ce-chloro-6-I3-(1-("trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2- pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (232 mg, 0.3068 mmol) was dissolved in dichloromethane (5.0 mL) and hydrochloric acid (4M in dioxane) (2.5 mL of 4M, 10, 00 mmol) was added to the mixture and allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2M sodium carbonate (5 mL) was added to bring the solution to pH - 10. Organic the layer was extracted with ethyl acetate (2 x 10 ml), washed with saline, dried over sodium sulfate and evaporated to dryness under reduced pressure.

Part B: The crude amine from Part A, potassium carbonate (235 mg, 1.70 mmol), cesium fluoride (75.3 mg, 0.4957 mmol), molecular sieves C of A, and dimethyl sulfoxide (7.0 mL) were added to the vial. . The vessel was purged with nitrogen, closed with a lid, heated to 150 "С and stirred for 16 hours. The reaction mixture was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with TM citric acid solution, and then with brine. The organic layers were separated, dried over sodium sulfate , evaporated and then purified by chromatography on silica gel (24 g column) using a gradient from 100 95 hexanes to 80 95 ethyl acetate to give 12,12-dimethyl-8-(3-11-(trifluoromethyl)) as an off-white solid cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10 ),6,8,19,21-hexane-2,2,4-trione (compound 15) (101.9 mg, 54 95). IN NMR (400 MHz, DMSO-ab) 5 12.51 (5, 1H) . 9 - 5.5

Hu, 1H), 6.92 (9, U - 8.2 Hu, 1H), 6.71 (a, U - 8.4 Hz, 1H), 6.16 (a, U - 2.7 Hz, 1H), 4.36 (d, U - 11.9 Hz, 2H), 3.92 (ai, U - 24.2, 10.9 Hz, 1H), 3.24 - 3.07 (t, 1H), 2.95 (9, U - 13.0 Hz, 1H), 2.78 - 2.64 (t, 1H), 2.22 - 2.08 (t, 1H), 1.86 (ai, y - 11.8, 5.0 Hz, 1H), 1.76 (aa, U - 15.9, 8.1 Hz, 1H), 1.65 - 1.54 (t, 6H), 1.51 (5, ЗН), 1.31 (ai, U - 24.7, 12.0 Gu, 1H), 1.10 (5, 4H). MO-IER t/: calc. 619.2189,

620.2 (M--1)k were found from Z; Holding time: 2.1 min. (Method of RH E).

Example 6: Preparation of 12,12-dimethyl-8-(3-C1-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18,23-pentaazatetracyclo |1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 21) and 12, 12-dimethyl-8-(3-C1-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclol 17.3.1.111 ,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 22) mm My o- they

From / to Zh le v, ha Le ish A Zh le

EZS EzZS EZS epaptsoteg 1 epaptsoteg 2

Stage 1: 12,12-dimethyl-8-(3-111-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo| 1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 21) and 12,12 -dimethyl-8-(3-111-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111, 14.05,10)htetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 22)

o oyu o oo b oo y m 5 U m" y: y m? У

Z A and Le Z A "Dn Z HER" LO le

EZS EzZS EzZS epapyoteg 1 epapyoteg 2

Racemic 12,12-dimethyl-8-(3-(C11-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo! /17,3,1,111,14,05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 15) (82.4 mg, 0.133 mmol) by chiral NKR chromatography using SpigaIiRak A5-H (column 250 X 21.2 mm, particle size 5 μm) with 20 95 acetonitrile (without modifier)/80 95 carbon dioxide as the mobile phase at 70 ml/ min. with obtaining the first eluted enantiomer /12,12-dimethyl-8-(3-11- (trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23 - pentaazatetracyclo!17,3,1,111,14,05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 21) (32.38 mg, 78 95) as an off-white solid; IN NMR (400 MHz, DMSO-a6) 6 12.51 (5, 1H), 8.22 (a, U - 2.7 Hz, 1H), 7.82 (9, U - 8.2 Hz, 1H), 7.72 - 7.67 (t, 1H) . 9 - 2.7 Hu, 1H), 4.36 (d, U - 11.9 Hz, 2H), 4.16 - 4.12 (t, 1H), 3.22 - 3.10 (t, 1H), 2.95 (90, 9 - 12.9 Hu, 1H), 2.74 - 2.68 (t, 1H), 2.20 - 2.03 (t, 1H), 1.86 (ad, 9 - 12.2, 5.0 Gu, 1H), 1.76 (ai, 9 - 10.3, 4.8 Hz, 1H), 1.60 (5, ЗН), 1.51 (5, ЗН), 1.28 (5, 4Н), 1.10 (5, 2Н), 0.67 (а, У - 5.1 Hz, 2Н), MO-

IER t/2 calc. 619.2189, found 620.2 (M--1) k; Holding time: 2.1 min. (Method LC E) and the second eluted enantiomer, 12,12-dimethyl-8-(3-111-(trifluoromethyl)cyclopropyl|Imethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 . enantiomer 2) (Compound 22) (34.58 mg, 83 9) as an off-white solid; 1H NMR (400 MHz, DMSO-ab) b 12.51 (5, 1H), 8.22 (y, Y - 2.8 Hz, 1H), 7.82 (a, Y - 8.3 Hz, 1H), 7.69 (y, Y - 3.6 Hz , 1H), 7.57 (I, U - 7.8 Hu, 1H), 7.05 (a, U - 7.2 Hz, 1H), 6.92 (a, 9 - 8.3 Hu, 1H), 6.71 (a, 9 - 8.5 Hz, 1H ), 6.16 (a, 9 - 2.8 Hz, 1H), 4.36 (d, U - 11.9 Hu, 2H), 4.14 (a, - 2.3 Hu, 1), 3.16 (5, 1H), 2.95 (y, U 2 13.4 Hu, 1H), 2.76 - 2.68 (t, 1H), 2.19 - 2.07 (t, 1H), 1.86 (aa, U - 11.6, 5.1 Hu, 1H), 1.75 (5, 1H), 1.60 (5, ЗН ), 1.51 (5, ZN), 1.28 (0.9 - 2.1 Hu, 4H), 1.10 (a, 9 - 2.7 Hu, 2H), 0.88 (5, 2H), MO-IER t/2 calc. 619.2189, found 620.2 (M--1)k; Holding time: 2.1 min. (Method of RH E).

Example 7: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19 ,24-pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 28) at 9)

Suten Zier 1 Sk Zier 2 vobzrtrv Zier Z «ori Zer4

Wg o mo" 9 "catch of vivr 5 la Zierb el Weert pradiai Zir 8 m, (c)

Vos-M MNa 7 B/U Zere on MN ov shchi vyvr 10

E at 00

M uv; we, who is in Shk

Zo

Stage 1: Ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate. oh oh oh oh

Purely Sk --

Hg

A solution of ethyl 2-oxocyclopentanecarboxylate (70 g, 449 mmol) in dry tetrahydrofuran (300 mL) was slowly added to a suspension of 67.6 g of sodium hydride in mineral oil (19.17 g, 540 mmol) in tetrahydrofuran (750 mL), which containing hexamethylphosphoramide (97 g, 540 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 hour. Dibromomethane (392 g, 250 mmol) was added and the reaction mixture was heated under reflux at 80 "C for 16 hours. The reaction mixture was allowed to cool to room temperature and diethyl ether (1000 mL) was added, and the organic layer was washed with water (5 x 500 mL ), dried over anhydrous sodium sulfate, concentrated and purified by chromatography on silica gel using 0-1095 hexane-ethyl acetate to give ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate (85 g, 7695) as a colorless oil. IN NMR (250 MHz, SOSIZ) 6 4.18 (d, y - 7.0 Hz, 7.25 Hz, 2H); 3.68 (4, y - 22.5 Hz,

In - 9.5 Hz, 2H); 2.58 - 2.00 (t, 6H); 1.25 (I, U - 7.75 Hz, ZN).

Stage 2: diethyl-2-methylenehexanedisate o o Te)

Sk voi ZY

Vg o

Potassium carbonate (79 g, 572 mmol) was added to a solution of ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate (85 g, 341 mmol) in dry ethanol (680 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, evaporated and purified by silica gel column chromatography using 0-55905 hexane-ethyl acetate to give diethyl 2-methylenehexanedioate (72.7 g, 98 95) as a colorless oil. 1H NMR (250

MHz, SOSIZ) 6 6.16 (5, 1H); 5.54 (5, 1H); 4.24 - 4.07 (t, 4H); 2.36 - 2.28 (t, 4H), 1.83 - 1.77 (t, 2H), 1.32 - 1.21 (t, 6H).

Stage 3: Diethyl 2-(2-methyl-2-nitropropyl)hexanedioate

Gee! (in)

1,8-diazabicycloundec-/-ene (23 g, 151 mmol) was added to a solution of diethyl 2-methylenehexanedioate (72.7 g, 340 mmol) and 2-nitropropane (36.3 g , 408 mmol) in dry acetonitrile (1000 mL) and the mixture was stirred at room temperature for 16 hours.

The mixture was evaporated, and the residue was dissolved in ethyl acetate (1000 mL) and washed with saturated ammonium chloride (500 mL). The organic phase was concentrated and purified by silica gel column chromatography using 0-10 90 hexane-ethyl acetate to obtain diethyl 2-(2-

Zo methyl-2-nitropropyl)hexanedioate (86 g, 84 95) in the form of a colorless oil. TIA NMR (250 MHz,

SOSIZ) 5 4.17 - 4.07 (t, 4H); 2.41 - 2.05 (t, 5H), 1.72 - 1.44 (t, AN), 1.56 (v, ZN), 1.51 (v, ZN), 1.28 - 1.21 (t, 6H).

Stage 4: 4-(4,4-dimethyl-5-oxopyrrolidin-2-yl)butyric acid ethyl ester

Her OE K

BYU 'advised -- with

A mixture of diethyl-2-(2-methyl-2-nitropropyl)hexanedioate (43 g, 141.7 mmol) and nickel suspension

Raney (12 g) in ethanol (860 ml) was heated at 80 °C for 18 h in a Parr reactor under 2 bar of hydrogen gas. Celite (50 g) was added and the resulting mixture was filtered. The solids were discarded and the filtrate was concentrated to give ethyl ether 4-(4,4-dimethyl-5-oxopyrrolidin-2-yl)butyric acid (31.2 g, 97 U) in the form of orange oil. The crude product was used for the next stage without additional purification. MO-IER tp/2 calculation 221.3, found 228.3 (M--1)k Retention time: 3.23 min (Method РХ 0).

Stage 5: 4-(4,4-dimethylpyrrolidin-2-yl)butan-1-ol 9) radiyl radium -- ж ю-

Lithium aluminum hydride (39.3 g, 1036) was added to a solution of 4-(4,4-dimethyl-5-oxopyrrolidin-2-yl)butyric acid ethyl ether (78.8 g, 345.3 mmol) in tetrahydrofuran (1200 mL). .0 mmol) in portions for 45 minutes, and the resulting suspension was heated under reflux in a nitrogen atmosphere for 18 hours. The cooled reaction mixture was carefully quenched with saturated sodium sulfate solution (100 mL) and the solid formed was filtered. The solids were discarded and the filtrate was concentrated in vacuo to give 4-(4,4-dimethylpyrrolidin-2-yl)butan-1-ol (51.5 g, 87 95) as a brown oil. The crude product was used for the next step without further purification. MO-IER n/2 calc. 171.28, found 172.3 (MA) k. Retention time: 1.05 min. (Method РХ 0).

Stage 6: tert-butyl ester of 2-(4-hydroxybutyl)-4,4-dimethylpyrrolidine-1-carboxylic acid radium pridnny -n---

To a solution of 4-(4,4-dimethylpyrrolidin-2-yl/butan-1-ol) (51.5 g, 301 mmol) in dichloromethane (400 mL) was added a solution of sodium bicarbonate (50.6 g, 602 mmol) in water (300 mL) followed by di-tert-butyldicarbonate (65.6 g, 301 mmol). The resulting biphasic mixture was stirred for 18 h at room temperature. The phases were separated and the aqueous phase was discarded. The organic phase was concentrated and purified by silica gel chromatography using 0 -45 95 hexane-ethyl acetate, to obtain tert-butyl ether 2-(4-hydroxybutyl)-4,4-dimethylpyrrolidine-1-carboxylic acid (57.2 g, 77 Fo) in the form of a clear oil. IN NMR (250 MHz , SOSIZ) 5 4.35 (I, 1H), 3.53 (t, 1H), 3.37 (t, 2H), 2.76 (t, 1H), 2.01-1.81 (t, 2H), 1.40-1.24 (t, 23H). MO-IER t/: calcd 271.4, found 272.4 (M--1) k Retention time: 4.67 min (Method РХ 0).

Stage 7: tert-butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate elone pradny OM5 - -ь-

To a solution of tert-butyl-4-(4-hydroxybutyl)-2,2-dimethylpyrrolidine-1-carboxylate (2.28 g, 8.401 mmol) in dichloromethane (19 ml) and triethylamine (8.0 ml) cooled to 0 "С , 57 mmol) was added dropwise to methanesulfonyl chloride (2.161 mL, 27.92 mmol). The reaction mixture was stirred for 20 h, allowing the reaction mixture to warm to room temperature after 1 h (the clear solution turned cloudy orange after 10 min).

The reaction mixture was quenched with ice water and dichloromethane, and then with saline solution. The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained material was dried in vacuum for 1 h to obtain tert-butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (2.9 g, 99 95) as a yellow oil. MSO-IER

From t/2 calculation. 349.1923, found 350.2 (M--1)x; Holding time: 1.82 min. (Method of RH E).

Stage 8: tert-butyl 4-(4-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate ele ele - - zh

Tert-butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (2.9 g, 8.298 mmol) was dissolved in a mixture of dioxane (60 ml) and ammonium hydroxide (60 ml 30 95 wt. / vol., 510 mmol). The mixture was heated to 50"C in a closed vessel for 18 h. Dioxane was concentrated under vacuum and dichloromethane (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography on silica gel (80-gram column) using the dichloromethane-methanol gradient method (containing 5 ml/liter of 30 95 ammonium hydroxide) (from 0 to 1595 methanol in dichloromethane) to obtain /tert-butyl-4-(4-aminobutyl)-2,2-dimethylpyrrolidine- 1-carboxylate (1.44 g, 64 95) as an off-white foam. 1H NMR (400 MHz, dmoo-ab) b 7.90 (5, 2H), 3.55 (ad, 9U - 18.7, 11.1 Hz, 1H) , 3.34 (5, 2H), 3.17 (c, 1H), 2.76 (aa,

U - 17.0, 9.5 Hz, 2H), 2.06 (5, 1H), 1.95 - 1.74 (t, 1H), 1.52 (i, U - 18.4 Hz, 2H), 1.39 (a, U - 9.9 Hz,

OH), 1.35 (5, 1H), 1.34 (in, 2H), 1.91 - 1.18 (t, 6H). MO-IER t/: calc. 270.23074, found 271.2 (Mae1)-k; Holding time: 1.21 min. (The method of RH is).

Stage 9: tert-butyl-2,2-dimethyl-4-(A-(b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate oo zB-I 0.9 with WMO

Vos-M MN» ate and, - - - - 5 - MN

Come on

In a 250 mL flask, b-fluoropyridine-2-sulfonamide (894 mg, 5.07 mmol) was combined in dimethyl sulfoxide (20 mL), followed by potassium carbonate (1.1 g, 8.0 mmol) and tert-butyl 4-(4-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.44 g, 5.33 mmol) under a nitrogen atmosphere and under reflux. The vessel was heated at 60 °C in an oil bath for 18 hours.

Potassium carbonate (1.1 g, 8.0 mmol) was added and heating was increased to 80 C for an additional 4 hours. After cooling, the reaction mixture was filtered, then diluted with ethyl acetate and washed with 1 M citric acid solution and then with saline solution.

The organic layers were separated, dried over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel (80-gram SOI O column) using a gradient from 100 95 hexanes to 75 95 ethyl acetate in hexane to obtain tert-butyl 2 as a white solid. 2 -Dimethyl-4-I(4-(b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (475 mg, 22 95). NR NMR (400 MHz, DMSO-ab) b 7.51 (aa , in - 8.4, 7.3 Hz, 1H), 7.07 (5, 2H), 6.94 (Her,

U - 5.7 Hz, 2H), 6.61 (a, y - 8.2 Hz, 1H), 3.54 (aa, U - 18.2, 8.5 Hz, 1H), 3.28 (ai, U - 12.6, 6.6 Gu, 2H), 2.78 ( ad, 9U - 19.7, 10.1 Hz, 1H), 2.07 (5, 1H), 1.94 - 1.80 (t, 1H), 1.52 (5, 2H), 1.44 (a, 15. 9U-12.2 Hz, 1H), 1.38 (y, U - 10.4 Hu, 9H), 1.35 (a, U - 10.9 Hz, 6H), 1.21 (a, U - 17.2 Hu, 4H). MO-

IER t/2 calc. 426.23007, found 427.2 (M--1); Holding time: 1.76 min. (Method of RH E).

Stage 10: tert-butyl 4-(A-C(6-Ce-chloro-6-I3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (o)

EZS EZS

2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (425 mg, 1.13 mmol) and carbonyl diimidazole (217 mg, 1 .34 mmol) were combined in tetrahydrofuran (7 ml) and stirred for 90 min at 50 "C. Then tert-butyl-2,2-dimethyl-4-(A-(b-sulfamoyl-2-pyridyl)amino) was added |butyl|pyrrolidine-1-carboxylate (475 mg, 1.11 mmol) followed by 1,8-diazabicyclo/5.4.FO)undec-7-ene (350 μL, 2.34 mmol), and the reaction mixture was heated at 50 "C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel (80-gram column) using gradient from 100 9o hexanes to 70 95

From ethyl acetate in hexane to obtain tert-butyl-4-(4-((6-Ce-chloro-6-(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-3 -carbonyl|sulfamoyl|-2- pyridylyamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (613 mg, 83 95) as a white solid. TIN NMR (400 MHz, DMSO-ab) b 12.80 (5, 1H), 8.41 (I, U - 3.0 Hz, 1H), 8.11 (a, - 8.4 Gu, 1H), 7.71 (a, U - 8.4 Hz, 1H), 7.61 (ai, y - 8.4, 7.3 Hz, 1H ), 7.22 (5, 1H), 7.16 (a, y - 7.0 Gu, 1H), 6.73 (a, U - 8.5 Hz, 1H), 6.18 (y, 9U - 2.9 Hz, 1H), 4.34 (I, U - 7.0 Hz, 2H), 3.54 - 3.42 (t, 1H), 3.22 (1.9 - 6.8 Hz, 2H), 2.72 - 2.63 (t, 1H), 2.08 (1, U - 7.1 Hz, 2H), 2.00 - 1.88 (t, 1H), 1.71 (Id, U - 11.2, 5.9 Gu, 1H), 1.53 - 1.45 (t, 2H), 1.40 - 1.34 (t, 9H), 1.25 (I, U - 11.6 Hz, 6H ), 1.20 - 1.18 (t, 1H), 1.17 (y, - 6.0 Hz, 4H), 0.98 - 0.92 (t, 2H), 0.88 (5, 2H). MO-IER t/2 calc. 783.27924, found 784.2 (MA1) k Retention time: 2.4 min (Method RH E).

Stage 11: 12,12-dimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,19, 24-pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21- hexane-2,2,4-trione (Compound 28) is a soluble Mt tot o-0 MM A Mn r ke; MN - Bad I'm in v

EZS

Part A: tert-butyl 4-I4-(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2- pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (538 mg, 0.686 mmol) was dissolved in dichloromethane (12 mL) and hydrochloric acid (4 M in dioxane) was added to the mixture (5 mL of 4 M, 20, 0 mmol) and stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure, re-dissolved in ethyl acetate, then aqueous 2 M sodium carbonate (5 ml) was added, obtaining a pH of -

10. Extracted with ethyl acetate (2 x 10 ml), washed with saline, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: Combine the materials from part A and potassium carbonate (474 mg, 3.43 mmol), cesium fluoride (156 mg, 1.03 mmol), molecular sieves 3 A, and dimethyl sulfoxide (11 mL) in a vial, purge with nitrogen, and cap , heated to 150 "C and stirred for 18 hours.

Cooled to room temperature. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel (40-gram column) using a gradient from 100 90 hexanes to 80 95 ethyl acetate in hexane to obtain 12,12-dimethyl-8-(3- 12-11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1( 23),5,7,9,20(24),21-hexane-2,2,4-trione (compound 28) (270 mg, 60 95) as a white solid. TN NMR (400 MHz, DMSO-ab) b 12.45 (5, 1H), 8.21 (a, U - 2.7 Hz, 1H), 7.86 (a, 9 - 8.3 Hz, 1H), 7.69 (I, U - 7.9 Hz , 1H), 7.23(a0.9 7.2

Hu, 1H), 6.93 (y, U - 8.3 Hz, 1H), 6.81 (a, 9 - 8.4 Hu, 1H), 6.12 (a, 9 - 2.7 Hz, 1H), 4.32 (I, U - 7.0 Hu, 2H), 3.51 (5, 2H), 3.30 (5, 1H), 2.76 (9, U - 15.3 Hz, 1H), 2.69 - 2.58 (t, 1H), 2.14 (a, U - 7.4 Gu, 1H), 2.08 (I, U - 7.0 Hu, 2H), 1.85 (ai, 9 - 11.6, 5.4 Hu, 1H), 1.56 (5, 2H), 1.55 (y, U - 3.3 Hu, 6H), 1.46 (5, 2H ), 1.26 - 1.16 (t, 2H), 0.96 (i, 9 - 5.7 Hz, 2H), 0.89 (5, 2H). MO-IER t/2 calc. 647.2502, found 648.2 (M--1)k; Holding time: 2.26 min. (Method of RH E).

Example 8: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19 ... 12,12-dimethyl-8-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo| 18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 30) 9 o 9 9 e at

Es. - z' -- z -- epapioteg 1 epapioteg 2

Stage 1: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (enantiomer 1) (Compound 29) and 12,12 -dimethyl-8-(3-(2-(1-

Zo (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23), 5,7,9,20(24) 21-hexane-2,2,4-trione (enantiomer 2) (Compound 30) at 9, at 00 at 0, certain at. sub

EZS a vod Ezs she tn EzS she tn

GI Bo epapboteg 1 Bo epapioteg 2

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)- 35 2Ab-thia-3,9,11,19 24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (compound 28) (204 mg, 0.3150 mmol ) were subjected to chiral liquid chromatography using a SpigaIRak A5B-N (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 96 acetonitrile:methanol (90:10)3)/70 90 carbon dioxide at 0.5 ml /min, giving as the first eluted enantiomer, 12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3 ,9,11,19,24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (enantiomer 1 ) (Compound 29) (94.1 mg, 91 95) as an off-white solid; MO-IER t/2 calcd. 647.2502, found 648.2 (M--1)g; Retention time: 2 , 27 min (method РХ E) and as the second eluted enantiomer 12,12-dimethyl-8-(3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,19 ,24-pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (compound 30) (90.0 mg, 87 9Uv) as an off-white solid; 1H NMR (400 MHz, DMSO-ab) b 12.45 (5, 1H), 8.21 (y, Y - 2.8 Hu, 1H), 7.86 (a, Y - 8.3 Hz, 1H), 7.69 (I, Y - 7.9 Hz . ), 4.32 (I, U - 7.0 Hz, 2H), 3.29 (aa, U - 4.7, 2.4 Hz, 1H), 2.86 - 2.69 (t, 1H), 2.63 (ai, U - 16.0, 11.6 Hz, 1H) . Hz, 6H), 1.47 (yes, U 5 22.2, 10.1 Hz, 2H), 1.26

- 1.16 (t, 2H), 0.96 (aa, U - 7.7, 3.7 Hz, 2H), 0.93 (a, U - 9.2 Hz, 1H), 0.88 (I, U - 5.68 Hz, 2H), MO-IER t /72 calc. 647.2502, found 648.2 (M'-1)k; Holding time: 2.27 min. (Method of RH E).

Example 9: Preparation of 12,12,17-trimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11 ... (Compound 35), 12,12,17-trimethyl-8-(3-12-(11-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 . ) (Compound 36), 12,12,17-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9 . diastereomers 1, enantiomer 1) (Compound 58), 12,12,17-trimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b- thia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8,19,21-hexaene-2,2, 4-trione (pair of diastereomers 1, enantiomer 2) (Compound 59), 12.1 2,17-trimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23- pentaazatetracyclo 17.3.1.111,14.05,10)htetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (Compound 60) and 12,12,17-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11, 18,23- pentaazatetracyclo!17.3.1.111,14.05,10)hetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (a pair of diastereomers 2, enantiomer 2) (Compound 61) 9) c) (o) |) o er 1 o to Zer2 o er z us Zievri ma Mo; at

Bivr 5 Vivr 6 (c) Zer7 M Ver 8 -- - as ---k -- o- --- on on on Ho o,o hu Mn more 9, MN; believe in; m ud: vyvro 0-4 i zlu ol z Mn 0-4 MTM To 0 - - -- o yo u ek 9) u Pe KD sh bu

M | - ; m ber M u m x M 4 X shk o-4MSM o Mn ---2 o-4M MM Mn 0-77 rad ve Kk sce ku ve Kk and ad sce Kk in ra aiazsegeoteg raiig 1 / diaziegeoteg raiig 2 ) |) ts M ts she,

FO sha is ХК o-4 MTM m o-4 MTM Mm 7 a Bad 7 and Bad diazeegeoteg raig 1, epapioteg 1 aiazsogeoteg raig 2, epapioteg 1 ) |) ц Z ц ше,

M what; day M that ; dn o-2 SMT Mm o-2 M TMM 7 and Bad 7 -and Bad diaz (egeoteg raig 1, epapyoteg 2 diaziogeoteg raikg 2, epapyoteg 2

Stage 1: (ZE)-3-(hydroxymethylene)-6-methyl-tetrahydropyran-2-one (sodium salt). about (in; du ma

To a suspension of sodium hydride (60% in mineral oil) (2.63 g 60 95 wt., 65.8 mmol) in diethyl ether (56 ml) was added absolute ethanol (300 μl), then a mixture of 6-methyltetrahydropyran-2-one (5.0 g, 43.80 mmol) and ethyl formate (6.0 mL, 74 mmol) were added dropwise at ambient temperature over 30 minutes. After the addition, the reaction mixture was stirred for 1 hour. at room temperature. The solid that formed in the mixture (sodium salt of the product) was collected by filtration, washed with diethyl ether and dried under high vacuum to give (ZE)-3-(hydroxymethylene)-6-methyltetrahydropyran-2-one (sodium salt) (7, 1 g, 99,965). MSO-IER t/2 calc. 142.06299, found 143.2 (M--T)k; Holding time: 0.64 min. (Method of RH E).

Stage 2: b-methyl-3Z-methylene-tetrahydropyran-2-one c) i) (c) and o, --k o

Ma (ZE)-3-(hydroxymethylene)-6-methyltetrahydropyran-2-one (sodium salt) (7.1 g, 43 mmol) was suspended in tetrahydrofuran (100 mL), treated with paraformaldehyde (4.2 g, 140 mmol) in nitrogen and the mixture was heated to 65 °C for 1 hour. The mixture was cooled in an ice water bath, quenched with a saturated aqueous solution of potassium carbonate (20 ml) and the organic phase was separated, then the aqueous phase was extracted with diethyl ether (4 x 10 ml). fractions were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation without heating. hexanes, with obtaining b-methyl-3-methylenetetrahydropyran-2-one (2.96 g, 55 90) as a colorless liquid. IN NMR (400 MHz, SOSIS) b 6.48 - 6.38 (t, 1H), 5.57 (4 , U - 2.7, 1.5 Gu, 1H), 4.49 (ada, U - 10.4, 6.3, 2.6 Hz, 1H), 2.71 (ddak o - 16.2, 5.0, 3.5, 1.3 Hu, 1H), 2.65 - 2.52 (t, 1H), 2.03 - 1.93 (t, 1H), 1.67 (adasd, y - 13.9, 12.4, 10.5, 5.1 Hu, 1H), 1.40 (a, 9 - 6.3 Hz, ZN). MO-IER t/» calc. 126.06808, found 127.0 (Ma1)w; Holding time: 0.66 min. (Method of RH E).

Stage 3: b-methyl-3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (o) (c) (o) --- (o)

MO» 2-nitropropane (2.6 mL, 29 mmol) was treated with 1,8-diazabicyclo(/5.4.FOundec-7-ene (550 μL, 3.68 mmol) and stirred for 5 minutes under a nitrogen atmosphere, then the solution b -methyl-3-

From methylenetetrahydropyran-2-one (2.96 g, 23.5 mmol) in acetonitrile (32 mL) was added dropwise at room temperature over 45 minutes. The solution was stirred at room temperature for 4 hours. The mixture was evaporated and the residue was then purified by chromatography on silica gel (120 g column) using a gradient of 100 90 hexanes to 60 95 ethyl acetate in hexane to give the product which was then dried in vacuo to give a clear oil which turned into a white solid. on settling, b-methyl-3-(2-methyl-2-nitropropyl)tetrahydropyran-2-one (4.32 g, 85 95). "IN NMR (400 MHz, SOSIZ) b 4.57 - 4.37 (t, 1H), 2.11 - 2.58 (t, 1H), 2.51 - 2.32 (t, 1H), 2.24 (da, 9 - 15.0, 6.9 Gu, 1H) . , 1.36 (aa, U - 6.2, 3.2 Hz, ZN). MO-IER t/72 calc. 215.11575, found 216.2 (M--1)-; Retention time: 1.11 min. (RC method IS).

Stage 4: 3-(3-hydroxybutyl)-5,5-dimethyl-pyrrolidin-2-one

Gee! |c) o -- ,ky A -- same them he

MO» b-methyl-3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (4.32 g, 20.07 mmol) was dissolved in ethanol (78 mL) and wet Raney nickel (1, 2 g, 20.45 mmol) in a nitrogen atmosphere.

Three cycles of vacuum/hydrogen were performed, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere (1 atmosphere) for 10 minutes. The suspension was then refluxed, heated to 60°C, and stirred at this temperature under a hydrogen atmosphere for 24 hours. It was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrates were combined and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (120 g column) using a shallow gradient from 100 95 dichloromethane to 10 95 methanol in dichloromethane to give 3-

(3-hydroxybutyl)-5,5-dimethylpyrrolidin-2-one (2.5 g, 67 95) as a white solid. 1N

NMR (400 MHz, DMSO-ab) b 7.63 (5, 1H), 4.36 (y, 9 - 4.7 Hu, 1H), 3.56 (1, 9 - 11.9, 6.0 Hz, 1H), 2.35 (da, U - 9.3 . Hu, 2H), 1.28 - 1.20 (t, 1H), 1.18 (5, ZN), 1.13 (5, ZN), 1.03 (ai, U - 6.2, 16 Hu, ZN). MO-IER t/2 calculation. 185.14159, found 186.2 (Ma-1)k; Holding time: 0.74 min. (Method of RH E).

Stage 5: 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol no n, on on

A solution of 3-(3-hydroxybutyl)-5,5-dimethylpyrrolidin-2-one (2.5 g, 13.49 mmol) in anhydrous tetrahydrofuran (37 mL) at room temperature under a nitrogen atmosphere. After the addition was complete, the reaction mixture was heated to reflux for 72 hours (two additional portions of lithium aluminum hydride (200 mg, 7.00 mmol) were added to the reaction mixture after 24 hours and 48 hours of reflux). The mixture was cooled in an ice water bath; tetrahydrofuran (25 ml) was added to the mixture, followed by the slow addition of aqueous saturated sodium-potassium tartrate tetrahydrate (Rochelle salt, 30 ml). The resulting mixture was intensively stirred for 2 hours at room temperature until a clear separation of the aqueous and organic phases was achieved; then the organic layer was separated and concentrated under vacuum. The residue was dissolved in dichloromethane (100 ml) and the resulting solution was washed with saline (2 X 15 ml). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol (1.6 g, 69,965) as a yellow oil. IN NMR (400 MHz, SOSIS) b 3.78 (aa, U - 11.9, 5.68 Hz, 1H), 3.14 (aa, U - 10.4, 7.6, 2.8 Hz, 1H), 2.59 (aa, U 2 11.0, 8.1 Hz, 1H), 2.24 - 2.07 (t, 1H), 1.87 - 1.78 (t, 1H), 1.73 (5, 2H), 1.54 - 1.37 (t, 4H), 1.37 - 1.21 (t, 1H), 1.21 - 1.13 ( t, 9H). MO-IER tp/2 calc. 171.16231, found 172.2 (Mae1)-k; Holding time: 0.53 min. (The method of RH is).

Stage 6: tert-butyl 4-(3-hydroxybutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate c)

B, da ni M on t, on

Di-tert-butyldicarbonate (2.4 mL, 10.45 mmol) and triethylamine (1.7 mL, 12.20 mmol) were added to a solution of 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol (1.6 g, 9.341 mmol) dissolved in dichloromethane (40 mL) at 0 "C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was washed with water (15 mL), saturated sodium bicarbonate (15 mL) and brine (15 mL), then the organic matter was extracted, dried over sodium sulfate, filtered, and the mixture was concentrated. tert-butyl-4-(3-hydroxybutyl)-2,2-dimethyl pyrrolidine-1-carboxylate (2.4 g, 95 965) as a clear oil. IN NMR (400 MHz, SOSIS) b 3.79 (5, 1H) , 3.75 - 3.56 (t, 1H), 3.00 - 2.77 (t, 1H), 2.18 - 2.04 (t, 1H), 1.89 (14, U - 12.3, 6.0 Hz, 1H), 1.63 (5, 1H), 1.53 (5, 5H), 1.49 - 1.43 (t, 12H), 1.38 (5, 1H), 1.34 (ai, 9 - 9.1, 4.5 Hz, 2H), 1.20 (I, U - 5.5 Hz, ZN).

MO-0ER t/» calc. 271.21475, found 272.2 (M--1) zhk; Holding time: 1.64 min. (Method of RH E).

Stage 7: tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate

Zo zhu"

Ka -- 3 - t M r 0-4 o on DA.

To a solution in dichloromethane (6 ml), cooled to 0 "С, tert-butyl-4-(3-hydroxybutyl)-2,2-dimethylpyrrolidine-1-carboxylate (346 mg, 1.275 mmol) and triethylamine (1.2 ml , 8.6 mmol) was added dropwise to methanesulfonyl chloride (350 μl, 4.52 mmol). The reaction mixture was stirred for 20 hours, allowing it to warm to room temperature in 1 hour (the clear solution turned cloudy-orange in 10 minutes). The reaction mixture was quenched with ice water and dichloromethane, followed by brine. The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was dried in vacuo for 1 h with obtaining tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-i-carboxylate (440 mg, 99595) as a yellow oil. MO-IER t/2 calculated 349.1923, found 350.1 (M--1) k Retention time: 1.8 min (Method RH E).

Stage 8: tert-butyl 4-(3-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Kk

Sasha Mn» schu -- --b2-n c) |c) yu 07? YES;

Tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (440 mg, 1.259 mmol) was dissolved in a mixture of dioxane (10 ml) and ammonium hydroxide (10 ml 30 95 wt./vol. , 85.60 mmol). The mixture was heated to 50"C in a closed vessel for 72 h. Dioxane was concentrated under vacuum and dichloromethane (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography on silica gel (24-gram column) using a gradient method of dichloromethane-methanol (containing 5 ml/liter of 30 95 ammonium hydroxide) (from 0 to 1595 methanol) with obtaining tert-butyl-4-(33-aminobutyl)-2,2 as a light yellow oil - dimethyl pyrrolidine-1-carboxylate (199 mg, 58 95).IN NMR (400 MHz, dimethylsulfoxide) 5 7.86 (s, 2H), 3.62-3.49 (m, 1H), 3.14 (dt , U - 17.3, 5.3 Hz, 1H), 2.79 (dd, y) - 19.2, 10.2 Hz, 1H), 2.08-1.97 (m, 1H), 1 .93-1.81 (m, 1H), 1.56 (ddd, U - 25.3, 14.2, 6.6 Hu, 1H), 1.49-1.43 (m, 1H), 1 ,42-1.33 (m, 15H), 1.24 (d, U - 5.9 Hz, 4H), 1.16 (d, U - 6.5 Hz, 2H).

Stage 9: tert-butyl-2,2-dimethyl-4-I(3-(b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate c) vu / them

MN» o, NM 2 M ku

IS

In a sealed 20 mL microwaveable vial, a solution of b-fluoropyridine-2-sulfonamide (526 mg, 2.986 mmol), tert-butyl-4-(3-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (800 mg, 2.958 mmol) and diisopropylethylamine (2.6 mL, 14.93 mmol) in dimethyl sulfoxide (8 mL) were stirred at 130 "C for 16 hours. The solvent was removed by i.p.

From fat, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, evaporated and purified by chromatography on silica gel using a 12 g column (gradient 0-85 95 ethyl acetate/hexanes) to obtain tert-butyl-2,2-dimethyl-4-I3-((6 sulfamoyl-2 -pyridyl)amino|butyl|pyrrolidine-1-carboxylate (490 mg, 38 95). "IN NMR (400 MHz, dmeo-ab) b 7.49 (ad, U - 8.4, 7.3 Hz, 1H), 7.03 (5, 2H), 6.93 (a, U - 7.2 Hz, 1H), 6.78 (4.9 - 8.1 Gu, 1H), 6.59 (9, U - 8.4 Hz, 1H), 4.02 (5, 1H), 3.53 (a, U - 10.0 Hu, 1H), 2.78 (yes, U - 18.9, 10.6 Hz, 1H), 2.02 (8.9 27.8 Hu, 1H), 1.88 (5, 1H), 1.55 - 1.42 (t, 2H), 1.42 - 1.29 (t, 16Н), 1.23 (5, ЗН), 1.11 (а,

In - 6.4 Gu, ZN). MO-IER t/2 calc. 426.23007, found 427.1 (M--1)x; Holding time: 0.66 min. (Method of RH A).

Stage 10: tert-butyl 4-(3-C(6-Ce-chloro-6-I3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (9)

Yi Bad Do u

M. her more Many (- 0-4 MM then Mn 5-5 My before what Kk and well

EzC Kk) 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (160 mg, 0.4258 mmol) and carbonyl diimidazole (69 mg, 0.4255 mmol) were combined in tetrahydrofuran (2.5 ml) and stirred for 120 min at 50 "C. Then, tert-

butyl-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (145 mg, 0.3399 mmol) and then 1,8-diazabicyclo(/ 5.4. Fundec-7-ene (110 μl, 0.7356 mmol), and the reaction mixture was heated at 50 "C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1

M with a solution of citric acid, and then with a saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by preparative

Reversed-phase HPLC using a C 18 column and Method 30-99 A1-B1 (acetonitrile-water with 5 mM hydrochloric acid) to give tert-butyl-4-I3-(6-C2-chloro-6-I(3- (2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (97 mg, 36 95) as a white solid MO-IER t/2 calcd 783.27924, found 784.2 (Ma-1)k Retention time: 2.44 min (RC Method E).

Stage 11: 12,12,17-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 1) ( Compound 35), 12,12,17-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11 ,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexaene-2,2,4-trione (pair of diastereomers 2 ) (Compound 36), 12,12,17-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9 . diastereomers 1, enantiomer 1) (Compound 58), 12,12,17-trimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b- thia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexaene-2,2, 4-trione (pair of diastereomers 1, enantiomer 2) (Compound 59), 12,12,17-trimethyl -8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1. 111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (Compound 60) and 12, 12,17-trimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23- pentaazatetracyclo 17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (Compound 61) o 0, ooo ooo o-yMM s Mn ---Zhi o- sn m rn 0-4 cm Mn ek - ved ek - vadi ek - vad ra aiaziegeoteg raiig 1 / aiavisgeoteg raiig 2 o o o 0, o- m km Mn 0-4 MN schi «7 -a water and «is - vad aiaziegeoteg raig 1, epapyoteg 1 aiavisgeoteg raig 2, epapyoteg 1 o i un o sn all Kk more! to ShCHA Kk a vodni aiazivegeoteg raig 1, epapioteg 2 aiazisgeoteg raig 2, epapioteg 2

Part A: tert-butyl 4-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2 -pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (97 mg, 0.1237 mmol) was dissolved in dichloromethane (2.0 ml) and hydrochloric acid (4 M in dioxane) was added to the mixture (1000 μl 4 M, 4,000 mmol) and stirred at room temperature for 3 h. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then aqueous 2 M sodium carbonate (5 ml) was added, obtaining pH - 10. The organic layer was extracted with ethyl acetate (2 x 10 ml), washed with saline solution, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: The materials from part A were combined with potassium carbonate (90 mg, 0.6512 mmol), cesium fluoride (30 mg, 0.1975 mmol), molecular sieves Z A, and dimethyl sulfoxide (2.0 mL) in a vial, purged with nitrogen, stoppered, heated to 150 "C and stirred for 18 hours.

Cooled to room temperature. The reaction mixture was filtered and then purified by reversed-phase preparative chromatography (column C18, from 2095 to 9995 acetonitrile (without modifier) in water (HmM hydrochloric acid)) to obtain as the first pair of diastereomers the eluted enantiomers /12,12,17-trimethyl -8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3. 1.111,14.05,10)hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (pair of diastereomers 1) (Compound 35) (9.0 mg, 22 95) in the form of an off-white solid; 1H NMR (400 MHz, DMSO-ab) b 12.62 (5, 1H), 8.21 (a, 9 - 2.68 Hu, 1H), 7.80 (a, 9 - 8.2 Hz, 1H), 7.57 (aa,

U - 8.5, 7.2 Hz, 1H), 7.05 (a, U - 7.2 Hu, 1H), 6.97 (a, U - 9.2 Hu, 1H), 6.91 (a, - 8.2 Hz, 1H), 6.68 (a,

U - 8.5 Hz, 1H), 6.11 (a, 9U - 2.8 Hz, 1H), 4.31 (her, y - 7.2 Hz, 2H), 4.17 (5, 1H), 3.10 (a, U - 9.4 Hz, 1H) . - 7.1 Hz, 1Н), 1.62 - 1.59 (t, ЗН), 1.56 (0, У - 12.9 Hz, 2Н), 1.51 (5, ЗН), 1.36 - 1.24 (t, 2Н), 1.04 (a, 9 - 6.3 Hz, ЗН), 0.95 (а, У - 4.6 Hz, 2Н), 0.90 (а, 9У - 11.1 Hz, 2Н); MO-IER t/2 calc. 647.2502, found 648.2 (Ma-1)j; Holding time: 2.25 min. (RX E method); apa a5 She 5esopa diastereomer raig Goy epapioteg5 se) vishe, 12,12,17-ishpityu!-8-(3-2-(1- (ogoteiNui)susiorgoruCeiiipohu)-1 H-ruga2o1-1-yl)-2Ab-thia -3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexaene-2,2,4 -trione (diastereomer 2) (Compound 36) (33.6 mg, 82 Us) az ap oi-m/pie zoiia; NMR (400 MHz, DMSO-ab) b 12.41 (5, 1H), 8.21 (a, U - 2.7 Hz, 1H), 7.65 (a, y - 7.8 Hz, 1H), 7.58 (ai, U - 8.5, 7.3 Hz, 1H), 7.20 (aa, U - 12.2, 7.3 Hz, 2H), 6.89 (0.9 - 8.2 Hz, 1H), 6.70 (a, U - 8.2 Hz, 1H), 6.10 (a, U - 2.7 Hu, 1H), 4.31 (I, U - 7.0 Hz, 2H), 3.65 (y, U - 5.0 Hu, 1H), 3.23 - 2.97 (t, 2H), 2.27 (da, U - 10.1, 511 Hu, 1H), 2.07 (y, U - 7.1 Hz, 2H), 1.89 (aa, U - 11.8, 5.8 Hz, 2H), 1.78 - 1.67 (t, 1H), 1.62 (5, ЗН), 1.58 (y,

U x 12.0 Hz, 1H), 1.52 (5, ЗН), 1.45 (ай, У - 14.0, 6.8 Hz, 1Н), 1.22 (а, У - 6.6 Hz, ЗН), 1.15 - 1.06 (t, 1Н), 0.97 - 0.93 (t, 2H), 0.89 (y, U - 11.4 Hz, 2H). IER-MS t/ calc. 6472502, found 648.2 (Ma1) same; Retention time: 2.29 min (RCH E method).

Part C: 12,12,17-trimethyl-8-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab6-thia-3,9,11,18 ,23-pentaazatetracyclo!17,3,1,111,14,05,10|tetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (a pair of diastereomers 1 ) (11.5 mg) was subjected to chiral separation by means of NKR chromatography using a SpigaIRak AB-N column (250 X 10 mm) (μm particle size) with 16 95 acetonitrile/methanol (90:10)/84 95 carbon dioxide as moving

From the phase at 10 ml/min. within 8.0 min. (injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10) to obtain the first eluted enantiomer of 12,12,17-trimethyl-8-(3-12-(11-trifluoromethyl)cyclopropyl) ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracycloyl17,3,1,111,14,05,10)tetracose-1(23),5( 10),6,8,19,21-hexane-2,2,4-trione (pair of diastereomers 1, enantiomer 1) (Compound 58) (2.6 mg, 45 9o;» 98 95 ee) in the form of dirty white solid; MO-IER tp/2 calc. 647.2502, found 648.2 (M.-1)-; Holding time: 2.25 min. (Method LC E) and the second eluted enantiomer, 12,12,17-trimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia -3,9,11,18,23-pentaazatetracycloyl17,3,1,111,14,05,10)tetracose-1(23),5(10),6,8,19,21-hexane-2,2 ,4-trione (pair of diastereomers 1, enantiomer 2) (Compound 59) (3.6 mg, 62 9o;» 98 95 ee) in the form of an off-white solid; MO-IER tp/2 calc. 647.2502, found 648.2 (M.-1)-; Holding time: 2.25 min. (Method of RH E).

Part 0: 12,12,17-trimethyl-8-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab6-thia-3,9,11,18 ,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5(10),6,68,19,21- hexane-2,2,4-trione (pair of diastereomers 2) (55 mg) was subjected to chiral separation by means of NKR chromatography using a SpigaIiRak A5-H column (250 X 10 mm) (particle size 5 μm) with a mobile phase of 16 95 acetonitrile/methanol (90:10)/84 95 carbon dioxide at a speed of 10 ml/min more than 8.0 min (injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10) with obtaining as the first eluted enantiomer 12,12,17-trimethyl-8-(3-12-P1 -(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23) ,5(10),6,8,19,21-hexane-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (compound 60) (17.9 mg, 64 95,» 98 95 her) in in the form of an inorganic white solid substance MO-IER t/2 calc. 647.2502, found 648.2 (Ma-1); Retention time: 2.3 min (LC E method) and as the second eluted enantiomer 12,12,17-trimethyl-8-(3-12-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole-1 - yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21- hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (compound 61) (18.1 mg, 65 95.» 98 95 ee) as an off-white solid; IN NMR (400 MHz, DMSO -ab) b 12.40 (5, 1H), 8.21 (a, U - 2.7 Hz, 1H), 7.59 (ad, U - 20.6, 12.9 Hz, 2H), 7.18 (9, y - 7.2 Hz, 2H), 6.89 (a, U - 8.1 Hz, 1H), 6.70 (a, 9 - 8.3 Hz, 1H), 6.10 (a, 9 - 2.6 Hz, 1H), 4.31 (her, U - 7.0 Hz, 2H), 3.63 (5 . ), 1.79 - 1.67 (t, 1Н), 1.62 (5, ЗН), 1.57

(ad, U - 12.1 Gu, 1H), 1.52 (5, ЗН), 1.49 - 1.39 (t, 1Н), 1.21 (а, 9 - 6.5 Hz, ЗН), 1.10 (da, 9 - 12.8, 4.4 Hz, 1H), 0.99 - 0.93 (t, 2H), 0.88 (5, 2H), MO-IER t/2 calc. 647.2502, found 648.2 (MA1) k; Holding time: 2.3 min. (Method of RH E).

Example 10: Preparation of 12,12-dimethyl-8-13-((2,2,3,3-tetramethylcyclopropyl)methoxy|-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18 ,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 42) o (o )

M on M. A Z er 1 m. Z Z Vier2 o--7 MN k no- o -- xx ) 0-5 (c) ---5 da bo,

TV iv) and M skh ny - I dm 7 o er sim soi M (and Zir otu sms

NM o o, ro) o o, re)

B: I still mV your sim m 5 in Mn o- MM m M, 7l el "NS

Stage 1: tert-butyl 3-((2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazole-1-carboxylate o (o)one m. Ж m. АЖ Ж

OIAO (39.53 g, 37.86 ml, 195.5 mmol) was added dropwise to a degassed solution of triphenylphosphine (51.28 g, 195.5 mmol) in toluene (360.0 ml) under a nitrogen atmosphere at 0 "C. . The mixture was stirred at 0 "C for 30 minutes, obtaining a white suspension. A solution of (2,2,3,3-tetramethylcyclopropyl)methanol (29.84 g 70 95 wt./wt., 162.9 mmol) and tert-butyl 3-hydroxypyrazole-1-carboxylate (30 g, 162 .9 mmol) in toluene (600.0 ml) dropwise at -5 9C for 2 hours. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was heated to 75 °C for 6 h and then allowed to cool to ambient temperature. The suspension was diluted with heptane (900 mL) and stirred at ambient temperature for 3 h. The suspension was filtered through celite and the precipitate was washed with 3 times 100 mL of heptane. The filtrate concentrated in vacuo to give a thick yellow oil. The crude product was chromatographed on a 750 g column of silica gel packed with dichloromethane, eluting with a gradient of 0-20 95 ethyl acetate/hexanes. The collected fractions containing the product were concentrated in vacuo to give an off-white solid substance, tert-butyl-3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazole-1-carboxylate (30.1 g, 6395).1H NMR (400 MHz,

SNiogoiogite-a) b 7.82 (y, 9 - 3.0 Hz, 1H), 5.88 (a, U - 2.9 Hz, 1H), 4.30 (a, U - 7.7 Hz, 2H), 1.61 (5,

OH), 1.12 (5, 6H), 1.04 (5, 6H), 0.70 (1, 9 - 7.8 Hz, 1H). MO-IER t/: calc. 294.19434, found 295.0 (M--1) zhk; Holding time: 2.19 min. (Method of RH B).

Stage 2: 3-(2,2,3,3-tetramethylcyclopropyl)methoxy|-1H-pyrazole c)

M. m. A Zh o-7 MN a o ---іyya V shcha

Zo To a solution of tert-butyl-3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazole-1-carboxylate (127 g, 431.4 mmol) in tetrahydrofuran (317.5 mL) and ethyl alcohol (635, 0 mL) was slowly added sodium hydroxide (431.4 mL 2 M, 862.8 mmol) and the mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure. The aqueous residue was diluted with water (400 mL) and extracted with methyl tert-butyl ether (762.0 mL).

The organic phase was washed twice with saline solution (2 x 300 ml), and the aqueous phase was extracted again with methyl tert-butyl ether (250 ml). The combined organic phases were dried, filtered and evaporated to give 3-(2,2,3,3-tetramethylcyclopropyl)methoxy|-1H-pyrazole (75 g, 89 95) as a viscous oil. IN NMR (400 MHz, DMSOO-ab6) 5 11.78 (5, 1H), 7.48 1.9 21 Hz, 1H), 5.65 (5, 1H), 4.05 (a, 9 - 7.7 Hz, 2H), 1.08 (5 , 6H), 1.00 (5, 6H), 0.67 (Her, U - 7.7 Hz, 1H). MSO-IER t/2 calc. 194.1419, found 195.0 (M'-1)k; retention time: 1.43 min. (Method of RH B).

Stage C: 2,6-dichloro-M-|((6-(3-(5,5-dimethylpyrrolidin-3-yl)propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide

IF) o, -Z dov Y uva and A

N hu ON 2 M. ah m-n uva same asom

A 2 o sim si MN (c)

Part A: To a solution of 2,6-dichloropyridine-3-carboxylic acid (200 mg, 1.042 mmol) in tetrahydrofuran (5 mL) was added di(imidazol-1-yl)umethanone (169.0 mg, 1.042 mmol) and the reaction mixture stirred for 90 min at 50 "C. Tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|Ipropyl|Ipyrrolidine-i-carboxylate (343.9 mg, 0.336 mmol) was added , and then 1,8 diazabicyclo|5.4.Fundec-7-ene (237.9 mg, 233.7 μl, 1.563 mmol), and the reaction mixture was heated at 50 "C for 18 hours. The reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride, and then with saline. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient of 100 95 hexanes to 10095 ethyl acetate to give tert-butyl-4-H3-(6-(2,6-dichloropyridine-3-carbonyl)sulfamoyl|-2-pyridylamino |Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (284 mg, 4695 ) in the form of an off-white sticky material. MO-IER t/72 calculated 585.15796, found 586.5 (M--1)x Retention time: 0.79 min (RC method A).

Part B: The material from Part A was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (1.782 g, 1.204 mL, 15.63 mmol) and stirred at room temperature for 5 hours.

The solvent was removed, the residue was dissolved in ethyl acetate, and the organic layers were washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed. The material was dried under vacuum overnight to give 2,6-dichloro-M-|((6-(3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-

Zo pyridyl|sulfonyl|pyridine-Z-carboxamide (233 mg, 10095) as an off-white sticky material. IN NMR (400 MHz, DMSO-a 6 ) 5 9.31 (5, 1H), 9.15 (5, 1H), 8.06 (y, U - 8.0 Hz, 1H), 7.73 (a, 9 - 8.1 Hz, 1H), 7.62 (aa, U - 8.5, 7.2 Hz, 1H), 7.17 (a, 9 - 7.2 Hz, 1H), 6.79 (a, U - 8.5 Hz, 1H), 3.34 (ad, U - 14.6, 5.7 Gu, 1H ), 3.24 (ad, y - 6.6, 4.1 Gu, 2H), 2.89 - 2.75 (t, 1H), 2.45 - 2.29 (t, 1H), 1.93 (da, U - 12.6, 7.7 Hz, 1H), 1.60 - 1.45 (t, ZN), 1.43 - 1.33 (t, 5H), 1.29 (5, ZN). MO-IER t/2 calc. 485.10553, found 486.5 (M'n1) same; Holding time: 0.5 min. (Method of RH A).

Stage 4: 8-chloro-12,12-dimethyl-2Abthia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10)tetracose-1(22),5,7,9,19 (23), 20-hexane-2,2,4-trione (hydrochloride salt) (Compound C) (c) o, iv pane o oo - H A y m? Sai sib sM sa | r N IF

MN Go: we are from Ul "NS

NM

A solution of 2,6-dichloro-M-|(6-(3-(5,5-dimethylpyrrolidin-3-yl)propylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (200 mg, 0.4112 mmol) in dimethyl sulfoxide (5.0 mL) and molecular sieves Z A were stirred at room temperature for 10 min. Then cesium fluoride (194 mg, 1.277 mmol) and potassium carbonate (1703 mg, 12.32 mmol) were added, and the reaction mixture was heated at 140 C overnight.The reaction mixture was filtered through a UMpaytap disc filter (Rigadies 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using an Ipa C18 column (2) (75 x 30 mm, particle size 5 μm), which sold by Rpepotepeh (art.: 00С-4252-00-АХ), run with a double gradient of 30-99 95 mobile phase B for 15.0 min. Mobile phase A - water (5 mM hydrochloric acid). Mobile phase B - acetonitrile Flow rate - 50 ml/min, injection volume - 950 μl, and column temperature - 2576 .3.1.111,14.05,10|hetracose-1(22),5,7,9,19(2 3),20-hexane-2,2,4-trione (hydrochloride salt) (76 mg, 38 95) as a white solid. 1H NMR (400 MHz, MeiNapo!-ad) b 7.69 (a, 9 - 7.9 Hz, 1H), 7.54 (da, 9 - 8.5, 7.3 Hz, 1H), 7.16 (a, 9 - 7.2 Hz, 1H), 6.67 (th, 9 - 8.5

Hu, 1H), 6.56 (a, U - 7.9 Hz, 1H), 4.14 - 3.93 (t, 1H), 3.26 - 3.15 (t, 1H), 3.09 - 2.98 (t, 1H), 2.78 (i,

In the same 10.0 Hu, 1H), 2.19 (da, 9 - 15.6, 5.6 Hu, 1H), 1.92 - 1.77 (t, 2H), 1.72 - 1.60 (t, 2H), 1.61 (5,

ЗН), 1.51 (5, ЗН), 1.49 - 1.34 (t, 2Н). MO-IER t/: calc. 449.12885, found 450.4 (M--1) t; Holding time: 1.92 min. (Method of RH B).

Stage 5: 12,12-dimethyl-8-13-(2,2,3,3-tetramethylcyclopropyl)methoxy|-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23 -pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 42) o bro (9) 3

Scandium triflate (6.073 mg, 0.01234 mmol) was added to a solution of 3-(2,2,3,3-tetramethylcyclopropyl)methoxy|-1H-pyrazole (11.98 mg, 0.06168 mmol) in dimethylsulfoxide (1 ml) and sodium hydride (10.2 mg, 50 Fo wt., 0.2125 mmol) at 0 "C in a nitrogen atmosphere. The reaction mixture was stirred for 30 min. 8-chloro-12,12-dimethyl-2A6-thia-3,9 ,11,18,23- pentaazatetracyclo!y17.3.1.111,14,05,10|hetracose-1(22),5,7,9,19(23), then 20-hexane-2,2,4 -trione (hydrochloride salt) (30 mg, 0.06168 mmol) and the reaction mixture was heated at 120 C for 16 hours. The reaction mixture was cooled to room temperature and quenched with a few drops of water. The resulting mixture was filtered through a UUPytap disc filter (rigadibs 25 TE) , and the filtrate was purified by reversed-phase HPLC-MS using a run with a double gradient of 50-99 95 mobile phase B for 15.0 min (mobile phase A - water (without modifier), mobile phase B - acetonitrile) to obtain 12, 12-dimethyl-8-(3-(2,2,3,3-tetramethylcyclopropyl)methoxy|-1H-pyrazo 1-1-yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23) ,20-hexane-2,2,4-trione (compound 42) (2.6 mg, 7 96). IN NMR (400 MHz, Spiogoitopt-a) b 8.19 (5, 1H), 8.07 (5, 1H), 7.57 (5, 2H), 7.51 (5, 1H), 6.58 (5, 1H), 5.96 (5, 1H), 4.28 (a, U - 7.8 Hz, 2H), 3.88 (Brg5, 1H), 3.41 - 3.27 (t, 2H), 3.21 (riv, 1H), 3.07 (riv, 1H), 2.61 (riv, 1H ), 2.08 (riv, 1H), 1.63 (v, 6H), 1.71 - 1.53 (t, ЗН), 1.26 (Bg5, 1H), 1.14 (y, 9 - 2.5 Hz, 6H), 1.07 (5, 6H) , 0.75 (Ii, 9 - 7.7 Hz, 1H). MO-IER tp/2 calc. 607.29407, found 608.5 (Ma-1)k; Holding time: 2.86 min. (Method of RH B).

Example 11: Preparation of 8-I(3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 43)

vo zier 1 vo zisr2 tre vir Z r vier 4 (c) 720 vivr5 on N ri Z vier 6 ---lLl yaya k Mu ---- o- iv) (o! o. em a o. M ra "M . и вер 8 и 0-4 -ert, Ton . | o -- pot, - s osM oi o uk o Chu; sh 2 5ier 9 sh 2- Has 9-0 Me 9-0 Mesa a. -verlo sh-- type-- Vos. MN 4-kh o Chu o OO tazh /afe

M. 2 M. vivr 11 N 2-0 MU s shchi o- MM M - Vos., MN -sh- MN towers

Stage 1: (1-cyclopropyl-2-methoxyvinylcyclopropane (o);

And - in

The 5000 mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary protective shell, a 9U-Ket temperature probe, a dropping funnel, a water-cooled reflux condenser, and a nitrogen inlet/outlet. (Methoxymethyl)utriphenylphosphonium chloride (97.3 g, 284 mmol) and tetrahydrofuran (375 mL) were charged to the vessel under nitrogen to give a white suspension. Stirring began and the vessel temperature was recorded at 19°C. Potassium tert-butoxide (31.85 g, 0.2838 mol) was then charged to the vessel, which was added as a solid in portions over 10 min, resulting in reddish-orange solution and exothermic reaction up to 21 "C. The mixture was continued to stir at room temperature for 30 minutes. Dicyclopropyl ketone (dicyclopropylmethanone) (25.0 g, 227.0 mmol) was charged into the dropping funnel, which was then added dropwise over 25 minutes, resulting in a gradual exotherm to 35°C. The resulting reddish-orange solution was allowed to cool gradually to room temperature, and then stirring was continued at room temperature for 4 hours. The reaction was then quenched by the dropwise addition of cold water (375 mL) over 25 minutes. The resulting biphasic mixture was transferred to a separatory funnel and left for 5 minutes. The aqueous layer was drained, and the organic the remaining layer was washed with brine (375 mL). The organic layer was removed and concentrated under reduced pressure to give a pale yellow oil that still contained some water. The mixture was diluted with ethyl acetate (500 mL), then transferred to a separatory funnel and partitioned with water (150 mL).The organic layer was removed, dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel . The filtrate was concentrated under reduced pressure to give a pale yellow oil with some solids (triphenylphosphine oxide). The mixture was diluted with hexane (500 mL) and then filtered through a Buchner funnel with a glass frit with a 40 mm layer of silica gel. The precipitate on the filter was washed by displacement with hexane (2 x 500 ml).

The filtrate was concentrated under reduced pressure to obtain /(1-cyclopropyl-2-

methoxyvinyl/ucyclopropane as a clear pale yellow oil (27 g, 0.1953 mol, yield 86 95).

MO-ER t/2 calc. 138.10446, found 138.0 (M--1)k; Holding time: 1.73 min. (Method of RH B).

Stage 2: 2,2-dicyclopropylacetaldehyde in tre

Aqueous hydrochloric acid (250 mL, 3 M, 750.0 mmol) was added to a solution of (1-cyclopropyl-2-methoxyvinyl)ucyclopropane (128 g, 709.4 mmol) in tetrahydrofuran (700 mL) and the mixture was stirred at ambient temperature for 16 hours, then stirred at 55°C for 4 hours and then allowed to cool to ambient temperature for 12 hours. The mixture was diluted with 500 mL of brine and the aqueous phase was separated. The aqueous phase was extracted with 500 mL of MTBE and the organic phases were combined. the phases were washed with 500 ml of brine, dried over magnesium sulfate, filtered and concentrated by weight. The resulting oil was diluted with 250 ml of MTBE and the residual water was removed using a separatory funnel. The organic phase was dried over magnesium sulfate, filtered and concentrated by weight, obtaining --2 ,2- dicyclopropylacetaldehyde (99.2 g, 96 Fo) as a light orange oil. 1H NMR (400 MHz,

SNiogoiogt-a) b 9.74 (y, 9 - 2.9 Hz, 1H), 1.06 (Id, U - 8.9, 2.9 Hz, 1H), 0.94 - 0.81 (t, 2H), 0.64 - 0.49 (t, 4H), 0.32 - 0.20 (t, 4H).

Stage 3: (E)-1-cyclopropyl-3-methoxy-allyl|cyclopropane roms

A 5000 mL round-bottom flask was equipped with a mechanical stirrer, heating hood, U-Cat temperature sensor, dropping funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. (Methoxymethyl)triphenylphosphonium chloride (116.8 g, 340.7 mmol) and tetrahydrofuran (423 mL) were charged to the vessel under nitrogen, which gave a white suspension. Stirring was started and the temperature in the vessel was recorded at 19 "C. Then potassium tert-butoxide (38.22 g, 340.6 mmol) was loaded into the vessel, which was added as a solid in portions over 30 minutes (12.74 g portions were added every 10 minutes), which led to a reddish-orange solution and exotherm to 40 "C. The mixture was continued to be stirred at room temperature for 30 min. At this moment, the temperature in the pot was fixed at 36 "C. Then into the drip

From the funnel, 2,2-dicyclopropylacetaldehyde (47 g, 6095 mabs./wt., contaminated with triphenylphosphine oxide from the previous stage, 227.1 mmol) was charged, which was then carefully added dropwise over 25 minutes, which led to the gradual release of heat and heating to 47 "Sb. The resulting reddish-orange solution was allowed to gradually cool to room temperature, and then continued to stir at room temperature for 15 hours. Then the reaction mixture (temperature in the container - 19 C) was quenched with cold water (1000 ml), which led to an exothermic exposure to 22"С. The mixture was continued to be stirred for 10 min. The resulting two-phase mixture was transferred to a separatory funnel and left for 5 min. The organic layer was removed, and the remaining aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic layers were concentrated under reduced pressure to give a dark amber oil that still contained some water. The mixture was diluted with ethyl acetate (500 ml), then transferred to a separatory funnel and separated with water (150 ml).

The organic layer was removed, washed with brine (200 mL), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel with a glass frit.

The filtrate was concentrated under reduced pressure to give a pale amber oil with some suspended solids (triphenylphosphine oxide). The mixture was diluted with heptane (500 ml) and then left at room temperature for 30 min. The suspension was filtered through a Buchner funnel with a glass frit and the precipitate on the filter was washed with heptane (2 x 100 ml).

The filtrate was concentrated under reduced pressure to a volume of approximately 200 ml. The pale amber solution was cooled to 0 °C in a crushed ice/water bath for 30 min, during which time more solids precipitated. The suspension was filtered through a Buchner funnel with a glass frit and the filter cake was washed with heptane (2 x 50 mL). The filtrate concentrated under reduced pressure to give KE)-1-cyclopropyl-3-methoxy-allyl|Icyclopropane (30 g, 87 95).1H

NMR (400 MHz, chloroform-a) b 6.31 (da, U - 12.7, 1.1 Hz, 1H), 4.68 (da, U - 12.7, 7.6 Hz, 1H), 3.51 (5, ЗН), 0.77 (di, U - 8.1, 5.0 Gu, 2H), 0.54 - 0.32 (t, 2H), 0.28 - 0.12 (t, 5H), 0.08 (da, 9 - 9.3, 5.3, 4.1 Hz, 2H).

Stage 4: 3,3-dicyclopropylpropanal

Aqueous hydrochloric acid (100 ml of 3 M, 300.0 mmol) was added to a solution of KE)-1-cyclopropyl-3-methoxy-allyl|cyclopropane (141 g, 555.7 mmol) in tetrahydrofuran (500 ml) and the mixture was heated to 50 "C for 2 hours. The mixture was cooled to ambient temperature and tetrahydrofuran was removed in vacuo. The residue was diluted with dichloromethane (700 mL) and the aqueous phase was separated (small emulsion). The organic phase was washed with 500 mL of brine, dried over magnesium sulfate, and filtered. To the filtrate was added MgCl2 (50 g, 525.11 mmol) and the mixture was stirred at ambient temperature for 12 h. The suspension was filtered through celite (the celite covers and needs to be scraped off). The filtrate was slightly cloudy and was washed with brine, dried over sulfate magnesium, filtered and concentrated to obtain 3,3-dicyclopropylpropanal (76.8 g, 100 95), IN NMR (400 MHz, chloroform-4) b 9.83 (t, 9. - 2.7 Hz, 1H), 2.71-2.39 (m, 2H), 0.73 (ddt, U - 5.5, 4.2, 2.9 Hz, ЗН), 0 .56-0.47 (m, 2H), 0.42 (dddd, U - 9.2, 7.6, 4.0, 2.6 Hz, 2H), 0.28-0.21 (m, 2H), 0.11-0.04 (m, 2H).

Stage 5: 3,3-Dicyclopropylpropan-1-ol rochi

To a suspension of lithium aluminum hydride (10.4 g, 266.9 mmol) in tetrahydrofuran (500 mL) was added dropwise a solution of 3,3-dicyclopropylpropanal (76 g, 549.9 mmol) in tetrahydrofuran (150 mL), providing gentle heating with Refrigerant. The mixture was stirred at ambient temperature for 2 h. The reaction was cooled in an ice bath and quenched by slow addition of water (10.4 mL, 577.3 mmol), then aqueous sodium hydroxide (10.4 mL, 4 M, 41.60 mmol), then water (31.2 mL, 1.732 mole). The suspension was filtered through celite, washed with tetrahydrofuran and concentrated ip massio to give 3,3-dicyclopropylpropan-1-ol (112 g, 73 90), NMR (400 MHz, chloroform-α). b 3.81 (1.9 - 6.9 Gu, 2H), 1.76 (d, U - 6.9 Hz, 2H), 0.63 (aK, U - 8.8, 8.0, 5.1 Hz, 2H), 0.50 - 0.34 (t, AN), 0.27 - 0.14 (t,

ZN), 0.14 - 0.02 (t, 2Н).

Stage 6: tert-butyl-3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (c) on N rya o. m prik ZSH Oto

Zo To tert-butyl-3-hydroxypyrazole-1-carboxylate (36.5 g, 198.2 mmol) in tetrahydrofuran (450 mL) under a nitrogen atmosphere was added 3,3-dicyclopropylpropan-1-ol (28.0 g, 199 .7 mmol) and triphenylphosphine (57.0 g, 217.3 mmol). RIAO (43.0 mL, 218.4 mmol) was added dropwise to the mixture, allowing the mixture to gradually warm to 45°C. After the addition, the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with hexane (450 mL) and removed from ca. 50 95 solvent ip mass, obtaining a suspension. The suspension was filtered using a medium frit and the solid was washed with hexane (3 x 50 mL). The filtrate was concentrated ip mass, obtaining an amber oil. The crude oil was diluted with dichloromethane and chromatographed on a 750 g silica gel column, eluting with a gradient of 0 95 to 40 95 ethyl acetate in hexane. Two major fractions were collected, the second fraction being the pure product. The first fraction contained triphenylphosphine and was re-chromatographed on a 750 g silica gel column, eluting with a gradient of 095 to 2595 ethyl acetate in hexane. the combined product from the second column with the product obtained from the first column gives tert-butyl-3-(3, 3-dicyclopropylpropoxy)pyrazole-1-carboxylate (39.0 g, 64 95). MO-IER t/2 calc. 306.19434, found 307.1 (M--1)k; Holding time: 2.26 min. (Method of RH B).

Stage 7: 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) o. M o to (in) M tes ogrto"

A solution of tert-butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (255 mg, 0.8322 mmol) and trifluoroacetic acid (325.0 μL, 4.218 mmol) in dichloromethane (1 mL) was stirred for 2 5 hours. Volatiles were removed in vacuo to give /3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) (266 mg, 100 95) as a colorless oil, which was used directly in the subsequent reaction. MS-IER t/:2 calc. 206.1419, found 207.2 (M--1)k; Holding time: 0.59 min. (Method of RH A).

Stage 8: tert-butyl /2-chloro-6-N3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carboxylate (6)

I s I sha: . ss M uv; - 0600 Y SMT nn ake chi

A mixture of tert-butyl 2,6b-dichloropyridine-3-carboxylate (220.0 mg, 0.8867 mmol), 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) (266.0 mg, 0. 8305 mmol), potassium carbonate (230 mg, 1.664 mmol) and 1,4-diazabicyclo|2.2.2)octane (20 mg, 0.1783 mmol) in dimethyl sulfoxide (10 mL) were stirred at room temperature for 15 hours.

The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saline, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using a gradient from 100 95 hexanes to 20 90 ethyl acetate in hexane to give tert-butyl-2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine -3-carboxylate (245 mg, 71 95) as a colorless oil. MO-IER t/2 calcd. 417.18192, found 418.4 (M--1)k; Retention time: 1.28 min. (Method RH

IN).

Stage 9: 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (c) iv) 9-X Ma - U 9-0 Moi

A solution of tert-butyl-2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carboxylate (245.0 mg, 0.5862 mmol) in trifluoroacetic acid (500.0 µL, 6.490 mmol) and dichloromethane (1.5 mL) were stirred for 4 h at room temperature. The solvent was evaporated, the residue was dissolved twice in tetrahydrofuran and concentrated in vacuo to give 2-chloro-6-N3-(3,3-dicyclopropylpropoxy) pyrazol-1-yl|pyridine-33-carboxylic acid (204 mg, 9695) as a white solid, which was used directly in the subsequent reaction. 1H NMR (400 MHz, Meishapo!-a4) b 8.47 - 8.32 (t, 2H ), 7.73 (y, U - 8.5 Hz, 1H), 6.03 (a, 9U - 2.9 Hz, 1H), 4.45 (I, 9 - 6.7 Hz, 2H), 1.98 (4, U - 7.0 Hz, 2H), 0.75 - 0.64 (t, 2H), 0.50 - 0.39 (t, 4H), 0.35 - 0.26 (t, 1H), 0.26 - 0.19 (t, 2H), 0.15 - 0.06 (t, 2H). MO-IER t/ 2 calcd 361.11932, found 362.3 (M--1)x Retention time: 0.8 min (RC Method A).

Stage-10: tert-butyl 4-(3-((6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridin-

Z-carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (c) to both

M. HK

0-4 cm so. - and o- MM ay three rt

M Vos.

In vom

Carbonyldiimidazole (224.1 mg, 1.382 mmol) and the mixture was stirred for 120 min at 50 "C. Then tert-butyl-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1- carboxylate (380 mg, 0.9211 mmol) in tetrahydrofuran (5 mL), then 1,8-diazabicyclo(/5.4.0)undec-7-ene (280.4 mg, 275.4 μL, 1.842 mmol) and the reaction the mixture was heated at 50 "C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:11 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by chromatography on silica gel , using a shallow gradient from 100 95 dichloromethane to 20 95 methanol in dichloromethane. idine-3-carbonyl|Isulfamoyl|-2-pyridylamino|propyl|- 2,2-dimethylpyrrolidine-1-carboxylate (356 mg, 51 95) as a white solid. 1H NMR (400 MHz, Spiogotogt-a) b 8.31 (a, U - 2.9 Hz, 1H), 8.02 (j, U - 8.4 Hz, 1H), 7.69 (a, U - 8.4 Hz, 1H), 7.58 - 7.50 (t, 2H), 6.55 (09, 9U - 7.7, 1.6 Gu, 1H), 5.95 (a, U - 2.9 Hz, 1H), 4.92 (5, 1H), 4.42 (i,

U - 6.9 Hz, 2H), 4.02 (da, U - 10.7, 7.3 Gu, 1H), 3.64 - 3.54 (t, 1H), 3.17 (1, U - 11.7 Hz, 1H), 2.88 (Her,

U - 10.7 Hz, 1H), 2.19 (a, U - 9.5 Hu, 1H), 1.97 (d, U - 6.8 Hz, 2H), 1.82 (0, U - 15.1, 7.6 Hz, 2H), 1.55 (aa, 9 - 16.3, 10.6, 5.0 Hu, 1H), 1.40 (5, 11H), 1.30 (5, ЗН), 1.25 (5, ЗН), 0.76 - 0.60 (t, 2Н), 0.55 - 0.40 (t, 4Н) . MO-IER t/ calc. 755.3232, found 756.5 (M'-1) k; Holding time: 0.6 min. (Method RH I).

Stage 11: 8-III-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3. 1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 43) o oo o oso

M. 4 Ma M. - M o-4 M M s nn liv t M xx otyti i

I

Solution of tert-butyl 4-I3-C(6-C2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|-2-pyridylIamino|propyl|- 2,2-Dimethyl-pyrrolidine-i-carboxylate (350 mg, 0.4627 mmol) in dichloromethane (2.917 mL) and trifluoroacetic acid (527.6 mg, 354.1 μL, 4.627 mmol) were stirred at room temperature for 4 h. Solvents was removed in vacuo, and the residue was dissolved in ethyl acetate. Washed with 2 mL of saturated aqueous sodium bicarbonate solution, the organic layers were collected and the solvent was removed in vacuo. The material was dissolved in dimethyl sulfoxide (17.50 mL) and molecular sieves ZA was added, cesium fluoride (210, 8 mg, 1.388 mmol) and potassium carbonate (191.8 mg, 1.388 mmol) and the reaction mixture was heated at 130 °C overnight. The reaction mixture was filtered through a filter disk

UmMpatap (rigadibes 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 20 95 to 80 95 mobile phase B for 15.0 min (mobile

From phase A - water (0.05 9% hydrochloric acid), mobile phase B - acetonitrile) with obtaining 8-

13-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111,14.05, 10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 43) (158 mg, 55965) as an off-white solid. TIA NMR (400 MHz,

SNiogoiogt-a) b 9.99 (5, 1H), 8.19 (a, Y - 2.8 Hz, 1H), 8.05 (a, Y - 8.4 Hz, 1H), 7.57 (I, Y - 7.8 Hz, 1H), 7.50 ( 9.9 - 7.2 Gu, 1H), 7.31 - 7.19 (t, 1H), 6.60 (a, U - 8.3 Hz, 1H), 5.91 (a, U - 2.8 Hz, 1H), 4.43 (i,

U - 6.8 Hz, 2H), 3.91 (5, 1H), 3.35, U - 8.7 Hz, 1H), 3.18 (y, U - 13.9 Hz, 1H), 3.03 (Her, U - 9.9 Hz, 1H), 2.60 (y, U - 18.4 Hz, 1H), 2.07 (da, U - 12.2, 7.8 Hz, 1H), 1.97 (d, U - 6.68 Hz, 2H), 1.62 (a, - 6.2 Hz, 11), 0.73 - 0.61 (t, 2H), 0.51 - 0.38 (t, 4H), 0.38 - 0.29 (t, 1H), 0.24 - 0.16 (t, 2H), 0.15 - 0.06 (t, 2H). MO-IER t/2 calc. 619.29407, found 620.4 (M--1)x; Holding time: 1.32 min. (The method of RH

IN).

Example 12: Preparation of 12,12-dimethyl-8-(3-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3, 9,11,23-tetraazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19 (23), 20-hexane-2,2,4-trione (enantiomer 1) ( Compound 48) and 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab6-thia-3,9,11 ,23- tetraazatetracyclo!|17.3.1.111,14.05,1d|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 49 )

what

B on? What so" fashion; "m Go Zer1 vos Go , o- m le si Ver? what is 5052

IS ". Z o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 9-0

IT! 9 IT; oh oh oh

M. 2 We 7 l M. 2 We M. 2 Ma

EZS Ezs Ezs epapiyoteg 1 epapiyoteg 2

Stage 1: tert-butyl 2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate to o, and

In lk nam uz

Me Vos

Sodium hydride was added portionwise to tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-i-carboxylate (257 mg, 0.9986 mmol) under nitrogen atmosphere in M,M-dimethylformamide (2.056 ml) (79.87 mg, 1.997 mmol) (caution: evolution of gas), and the mixture was stirred at room temperature for 20 min. Then b-fluoropyridine-2-sulfonamide (175.9 mg, 0.9986 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours and 20 minutes, then sodium hydride (23.96 mg, 0.9984 mmol) was added ( carefully: release of gas) and the resulting mixture was stirred for 20 min, then poured into 1 n. citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a clear oil which was purified by silica gel chromatography using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl //2,2-dimethyl-4- 13-(b-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate (275.2 mg, 67 90). MO-IER t/72 calc. 413.19846, found 414.2 (Ma-1)f; Holding time: 0.69 min. (Method of RH A).

Stage 2: tert-butyl 4-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|oxy|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (in 9 ooo

Ame I ovos the 5th -- : t Am he Go gayy x Y still Eight o

In a bottle with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (96.86 mg, 0.2578 mmol) and carbonyl diimidazole (45.81 mg, 0.2825 mmol) were combined in tetrahydrofuran (1.53 mL) and stirred for 120 min at 50 C with the lid open. Tert-butyl-2,2-dimethyl-4-I3 was then added -((b-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate (193.8 mg, 0.2578 mmol) in tetrahydrofuran (2.04 mL) followed by the addition of 1,8-diazabicyclo/5.4. F1undec-7-ene (80.81 mg, 79.38 μl, 0.5308 mmol) and the reaction mixture was heated at 50 °C for 16 hours. The reaction was diluted with ethyl acetate and washed with TM citric acid solution, and then with brine.

The organic phases were separated, dried over sodium sulfate, filtered and evaporated, then

Zo was purified by silica gel chromatography using a shallow gradient from 100 95 dichloromethane to 2095 methanol/dichloromethane. The product is eluted together with some impurities. Fractions containing the product were combined and repurified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate,

obtaining tert-butyl 4-I3-C(6-C2-chloro-6-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridyl|oxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (64.7 mg, 33 95). MO-IER t/2 calcd. 770.2476, found 771.2 (Ma-1)g; Time retention: 0.94 min (method RH A).

Stage 3: 2-chloro-M-I((6-I(3-(5,5-dimethylpyrrolidin-3-yl)upropoxy|-2-pyridyl|sulfonyl|)-6-(3-(2-

P-"(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide ooo ooo9o

GU GU xx m? skh t m xx povo e" 0-5 7 Me 0-57 Me m o ony o

Tert-butyl 4-I3-C6-Ce-chloro-6-I3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridyl|oxy |propyl|-2,2-dimethylpyrrolidine-1-carboxylate (132.5 mg, 0.1718 mmol) was dissolved in dichloromethane (578.2 μl) and trifluoroacetic acid (898.7 mg, 607.2 μl, 7.882 mmol), and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The organic layer was washed with a small amount of brine, then dried (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-M-(6-(3-(5,5-dimethylpyrrolidine-

3-yl)upropoxy|-2-pyridyl|sulfonyl|-6-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (110 mg, 95 95). MSO-IER t/2 calculated 670.1952, found 671.2 (Mat) zhk;

Holding time: 0.64 min. (Method of RH A).

Stage 4: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11 ,23-tetraazatetracyclo!| 1 7.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 40) 7 ch? oodo xx M t M: o-y M M s 6622 M. r M sh- o-7Й M MM i To

EzS

To a solution of 2-chloro-M-(6-(3-(5,5-dimethylpyrrolidin-3-yl)propoxy|-2-pyridyl|sulfonyl|)-6-(3-(2-P-"trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|pyridine-33-carboxamide (126.6 mg, 0.1886 mmol) in dimethylsulfoxide (5.063 ml) was added potassium carbonate (130.3 mg, 0.9430 mmol), cesium fluoride (34 .38 mg, 0.2263 mmol) and a small amount of molecular sieves Z A. The resulting mixture was closed and heated to 150 °C for 6.5 hours, then cooled to room temperature and stirred overnight. Then the mixture was heated to 165 °C for 90 minutes, then cooled to room temperature, diluted with ethyl acetate and washed

With 11 saturated aqueous MNASI/1 M citric acid, then saline solution. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil, which was purified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate (the product eluted after reaching 100 95 ethyl acetate) to give 12,12-dimethyl-8 -(3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11,23-tetraazatetracycloi|17.3.1.111,14.05,10 |hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 40) (58.2 mg, 48,965) as a white solid. MO-IER n/2 calc. 634.2185, found 635.2 (MAT) k; Holding time: 2.29 min. (Method of RH B).

Stage 5: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11 ,23-tetraazatetracyclo!| 1 7.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 48) and 12,12 -dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab6-thia-3,9,11,23-tetraazatetracyclo! |17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 49) boron oo 79 s m' 5. he zi zm o zi zmu more 5 I 5 gai mogu

ЕС ЕЗС Езс epapboteg 1 epapboteg 2

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3,9,11, 23-tetraazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (compound 40) (45,3 mg, 0.07052 mmol) was subjected to chiral separation by NCR chromatography using SpPigaiRak AB-N (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 25 95 acetonitrile/methanol (90:10)/75 95 carbon dioxide of carbon at ml/min for 8.0 min. (injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10)) as the first eluted enantiomer. 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab6-thia-3,9,11,23- tetraazatetracyclo !|17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione 10 (enantiomer 1) (Compound 48) (22 .20 mg, 97 95) in the form of a white solid; MO-IER Ip/7 div. 634.2185, found 635.0 (M--1)f; Retention time: 2.30 min (LC method B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-12-11-trifluoromethyl)cyclopropyl|vethoxy)-1H-pyrazol-1-yl) -18-oxa-2Ab-thia-3,9,11,23-tetraazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2 ,2,4-trione (enantiomer 2) (compound 49) (22.33 mg, 100 95) as a white solid; IN NMR (400 MHz, DMSO-ab) b 12.81 (5, 1H), 8.21 (a, U - 2.68 Hz, 1H), 8.01 (I. 9 - 7.9 Hu, 1Hn), 7.86 (a, U - 68.2 Hu . ), 5.17 (Y, U - 12.1 Hz, 1H), 4.32 (I, U. - 7.0 Hu, 2H), 4.11 (9.9 2 6.5 Hu, 1H), 3.93 (y, 9U 2 11.1 Hz, 1H) . Gu, 2H), 1.60 (5, ZN), 1.51 (5, ZN), 1.00 - 0.93 (t, 2H), 0.92 - 0.85 (t, 2H), MO-IER t/2 calc. 634.2185, found 635.1 (M--1)j; Holding time: 2.29 min. (Method of RH B).

Example 13: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo |17.3.1.111,14.05,1O|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 53)

Wed Wed Wed Wed Mon

And what? what about us

II Vera Vos Kt o sho; Zer5

eighth h h -80--

M in va

Ii du 7 du ooo and M B M Ya o ve; Van (e; pa; Ver M. SOS sia a Vosm v a NM 5-2 SHY

LEA in

Stage 1: tert-butyl 2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate

N

Dess-Martin periodate (9.95 g, 23.46 mmol) was added to a stirred solution of tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-i-carboxylate (5.20 g, 2020 mmol) in

of anhydrous CH2CI2 (40 mL) at 0"C (ice bath) under a nitrogen atmosphere. Over 15 minutes, the reaction mixture was allowed to warm to ambient temperature (and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (200 mL) and slowly added saturated aqueous sodium bicarbonate (100 mL) (to reduce evolution of carbon dioxide gas). Then 1095 sodium thiosulfate (50 mL) was added and stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2 x 100 mL) . The combined organic layers were washed with saline solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. The crude product was purified by medium-pressure silica gel chromatography (silica gel column 330 g, 5-35 95 ethyl acetate in hexane for 35 min) to obtain the desired tert-butyl-2,2-dimethyl-4-(3-oxopropyl)pyrrolidine carboxylate (3.96 g, 77 90) as a transparent of a viscous substance, tert-butyl-2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate (3.96 g, 77 96). "YAN NMR (400 MHz,

Meipapo!-a4) 6 4.48 (I, 9 - 5.4 Hz, 1H), 3.66 (ai, U - 11.2, 6.9 Hu, 1H), 2.87 (d, U - 10.7 Hu, 1H), 2.31 (9 - 7.6 Hu , 1H), 2.22 - 2.07 (t, 1H), 1.95 (aa, y - 17.2, 12.1, 6.1 Hz, 1H), 1.66 (d, U - 7.9 Gu, 1H),

1.62 - 1.55 (t, 1H), 1.54 - 1.48 (t, 2H), 1.47 (5, AN), 1.43 (5, 6H), 1.41 (5, 2H), 1.31 (5, ЗН). MSO-IER t/72 calc. 255.18344, found 256.2 (M--1) k; retention time: 1.57 min. (Method of RH B).

Stage 2: tert-butyl 4-but-3-ynyl-2,2-dimethyl-pyrrolidine-1-carboxylate (c) n

Potassium carbonate (1.62 g, 11.72 mmol) followed by the dropwise addition of (1-dimethoxyphosphoryl-2-oxopropylidene)iminoammonium (12.5 mL of 10 95 wt./vol., 6.473 mmol). After completion of the addition, the mixture was warmed to room temperature and stirred for 4 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1X). The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried (sodium sulfate), filtered, and concentrated to a clear oil, which was purified by silica gel chromatography using a gradient of 100 95 hexanes to 50 95 ethyl acetate in hexanes to give tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (1.15 g, 88 965). MSO-IER t/2 calculated 251.18852, found 252.2 (M--1)g; Retention time: 1.96 min. TN NMR (400 MHz,

SOSIZ) b 3.82 - 3.56 (t, 1H), 2.99 - 2.80 (t, 1H), 2.35 - 2.23 (t, 1H), 2.21 (da, 9 - 9.5, 4.6 Hz, 2H), 1.96 (5, 1H) .

Stage C: tert-butyl 2,2-dimethyl-4-I4-(3-sulfamoylphenyl)but-3-ynyl|pyrrolidine-1-carboxylate

Zue in NM od: yo (3.

NM

And VosM

Nitrogen was bubbled through a stirred mixture of 3-iodobenzenesulfonamide (308.0 mg, 1.088 mmol), tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (156.3 mg, 0.6218 mmol) ,

РІАА(РРИЗ3)2СИ2 (26.19 mg, 0.03731 mmol), copper iodide (11.84 mg, 0.06218 mmol) and M,M-dimethylformamide (1.563 mL) in a vial for 5 minutes, then M- isopropylpropan-2-amine (69.21 mg 95.86 μl, 0.6840 mmol), and the vial was sealed and stirred at 50 "C for 2.5 h, then cooled to room temperature and stirred overnight. Cooled to room temperature temperature and poured into water (200 ml) and extracted with dichloromethane (2 x 100 ml), combined organic layers, washed with water (2 x 100 ml), dried (magnesium sulfate), filtered and concentrated to an orange oil, which was purified

Chromatography on silica gel using a gradient of 10095 hexanes to 100 95 ethyl acetate gave tert-butyl-2,2-dimethyl-4-(4-(3-sulfamoylphenyl)but-3-ynyl|pyrrolidine-1-carboxylate (307, 9 mg, 92 90) in the form of a yellow oil. MO-IER t/: 2 calc. 406.19263, found 407.2 (M-AT)g; Retention time: 0.71 min. (Method RH A).

Stage 4: tert-butyl 2,2-dimethyl-4-(4-(3-sulfamoylphenyl)butyl|pyrrolidine-1-carboxylate dme 5 ode) nom I

NOM

Vos

VosM M

Platinum oxide (65.20 mg, 0.2871 mmol) followed by the addition of EN (2.188 ml) and nitrogen was bubbled through the mixture for 1 min, and then hydrogen was bubbled through the mixture for 5 min. Then the mixture was closed with a hydrogen balloon and stirred for 3 hours. Nitrogen was blown, added celite, stirred for 1 min, then filtered through a pad of celite The filtrate was concentrated to tert-butyl 2,2-dimethyl-4-(4-(3-sulfamoylphenyl)butyl|pyrrolidine-1-carboxylate (320.4 mg, 82 95) , orange oil, which was directly transferred to the next stage MO-IER t/2 calcd. 410.22394, found 411.3 (MA) k; Retention time: 0.73 min. (Method RH A).

Stage 5: tert-butyl 4-I(4-I3-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|phenyl |butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

With chu o oo

Abe I M-- Mem M so what shchi Ot, v v osM

In a bottle with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (95.96 mg, 0.2554 mmol) and carbonyl diimidazole (41.41 mg, 0.2554 mmol) were combined in tetrahydrofuran (1.00 mL) and stirred for 120 min at 50 C with the lid open. Tert-butyl-2,2-dimethyl-4 -|4-(3-sulfamoylphenyl)butyl|pyrrolidine-1-carboxylate (69.9 mg, 0.1703 mmol) in tetrahydrofuran (1.338 mL), followed by 1,8-diazabicyclo(/5.4.0)undec-7 -ene (50.93 μL, 0.3406 mmol), and the reaction mixture was heated at 50 "C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:11 saturated aqueous ammonium chloride/brine solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a shallow gradient from 100 95 dichloromethane to 20 95 methanol/dichloromethane to obtain tert-butyl 4-(4-(3-C(2-chloro-6-I) (3-(2-

P-«(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|phenyl|butyl|- 2,2-dimethyl-pyrrolidine-1-carboxylate (110.5 mg, 84 95) in in the form of a white solid. MO-IER t/2 calc. 767.27313, found 768.2 (M--1) k; retention time: 0.95 min. (Method of RH A).

Stage 6: 2-chloro-M-I(3-(4-(5,5-dimethylpyrrolidin-3-yl/butylIphenyl|sulfonyl-b-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole- 1-yl|Ipyridine-Z-carboxamide (salt of trifluoroacetic acid)

Her ZU Y ZU y: M y: M sSOGO. . SO 0-4 s 9-0 We ss for Vosm vs Kk -- NM "TA

tert-butyl 4-I4-I3-C2-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|phenyl|butyl|-2 ,2-dimethyl-pyrrolidine-1-carboxylate (110.5 mg, 0.1438 mmol) was dissolved in dichloromethane (482.2 μl) and trifluoroacetic acid (508.3 μl, 6.598 mmol) was added to the mixture and stirred at room temperature within 40 min.

The mixture was concentrated to dryness under reduced pressure, dissolved in sat. aq. sodium bicarbonate and ethyl acetate and the layers were separated. The aqueous layer was neutralized with saturated aq

With ammonium chloride and extracted with ethyl acetate. The organic fraction was dried (sodium sulfate), filtered, and concentrated to an orange oil, which was filtered and purified using the reversed-phase HPLC-MS method using a column I Ipa C 18 (2) (75 x 30 mm, particle size 5 μm) from Rpepotepeh (art.: 00С-4252-00-АЧ) and run with a double gradient from 1-99 95 mobile phase B in 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature same as 2575) Obtaining 2-chloro-M-I3-(4-(5,5-dimethylpyrrolidin-3-yl/butylIphenyl|sulfonyl) -b-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (salt of trifluoroacetic acid) (104.5 mg, 93 965). MO-IER t/72 calculated 667.2207, found 668.2 (M.-1) k, retention time: 0.67 min (Method RH A).

Stage 7: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 53)

(c) ra o to ye5 M TV

M | | n g M 0-5 7 M' sei 6066Й6Й2Й2ОО20 M. 2 - o-4 MOM Mm all m 7 -Й

EzS "TEA

To the solution // 2-chloro-M-I3-(4-(5,5-dimethylpyrrolidin-3-yl)butylIphenyl|sulfonyl-6-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol- Potassium carbonate (119.2 mg, 0.8625 mmol), cesium fluoride (26.22 mg, 0.1726 mmol) and a small amount of molecular sieves Z A. The resulting mixture was stoppered and heated to 165 "C for 6 hours.

Then the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil, which was purified by silica gel chromatography using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate to give 12,12-dimethyl-8-(3-12-I11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|1 7.3.1.111,14.05,10)hetracose-1(22),5,7 ,9,19(23),20-hexane-2,2,4-trione (compound 53) (46.5 mg, 51 95) as a yellow solid. 1H NMR (400 MHz, DMSO-ab) b 12.44 (5, 1H), 8.21 (a, U - 2.8 Hz, 1H), 7.84 (5, 1H), 7.81 (5, 1H), 7.78 - 7.74 (t, 1H), 7.59 (5, 2H), 6.93 (y, 9 - 8.2 Hu, 1H), 6.12 (a, 9 - 2.68 Hu, 1H), 4.31 (I, U - 7.0 Hu, 2H), 2.75 (5, ЗН), 2.65 (5, 1Н), 2.08 (I, 9 - 7.0 Gu, ЗН), 1.82 (Id, У - 13.9, 12.7, 6.0 Hz, 2Н), 1.59 (5, ЗН), 1.53 (5, 1Н ), 1.51 (5,

ЗН), 1.47 (5, 2Н), 1.14 (а, У - 8.7 Hz, 1Н), 1.01 - 0.93 (t, ЗН), 0.90 - 0.86 (t, 2Н), 0.72 (5, 1Н). MO-

IER t/2 calc. 631.244, found 632.1 (M--1); Holding time: 2.44 min. (Method of RH B).

Example 14: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11-triazatetracyclo |17.2.2.111,14.05,10|hetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (enantiomer 1) (compound 54) and 12,12-dimethyl- 8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|17.2.2.111,14.05,10| tetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (enantiomer 2) (compound 55) oo nm? 9, oo oo 2! -8 mod i nab? Vivr1 From vyvr2 and of Zivr Z

Shchi Iv and o- Meta 0733237

Vosm Vosm v - 2 9 y m a 9, 0-47 a iy m. Zh n iy v ta VosM oi She i v NM 9oo ooo 9oo hi I rey w sh w t w sh epapboteg 1 epapioteg 2

Stage 1: tert-butyl 2,2-dimethyl-4-I(I4-(4-sulfamoylphenyl)but-3-ynyl|pyrrolidine-1-carboxylate 9, oo Nam"

VosM 8

Same NOM, same BO

Hg

8 mM nitrogen was bubbled through a stirred mixture of 4-bromobenzenesulfonamide (256.9 mg, 1.088 mmol), tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (156.3 mg, 0.6218 mmol ),

РІАА(РРИЗ3)2СИ2 (26.19 mg, 0.03731 mmol), copper iodide (11.84 mg, 0.06218 mmol) and M,M-dimethylformamide (1.563 mL) in a vial for 5 minutes, then M- isopropylpropane-2-amine (69.21 mg, 95.86 μL, 0.6840 mmol), and the vial was sealed and stirred at 50°C for 75 minutes, then cooled to room temperature and stirred overnight. Cooled to room temperature and poured into water (200 ml) and extracted with dichloromethane (2 x 100 ml), combined organic layers, washed with water (2 x 100 ml), dried (magnesium sulfate), filtered and concentrated to an orange oil, which was purified by chromatography on silica gel using a gradient from 100 90 hexanes to 100 95 ethyl acetate to give tert-butyl-2,2-dimethyl-4-(4-(4-sulfamoylphenyl)but-3-ynyl|pyrrolidine-1-carboxylate (192.5 mg , 76 95) as a white solid. MO-IER Ip/2 calcd. 406.19263, found 407.1 (M--1)k; Retention time: 0.71 min. (Method RH A).

Stage 2: tert-butyl 2,2-dimethyl-4-(4-(4-sulfamoylphenyl)butyl|pyrrolidine-1-carboxylate vd oo

Nam nom?

BO ---w

VosM

VosmM

Palladium oxide (53.75 mg, 0.2367 mmol), followed by EN (1.804 mL) and nitrogen was bubbled through the mixture for 1 min, then hydrogen was bubbled through the mixture for 5 min. The mixture was then sealed with a hydrogen balloon and stirred for 3 h.

Purged with nitrogen, Celite was added, stirred for 1 min, then filtered through a layer of Celite.

The filtrate was concentrated to tert-butyl-2,2-dimethyl-4-(4-(4-sulfamoylphenyl)butyl|pyrrolidine-1-carboxylate (179.5 mg, 92 95), an off-white solid. /2 calcd 410.22394, found 411.2 (M.--1)k Retention time: 0.75 min (RH Method A).

Stage 3: tert-butyl 4-(4-(4-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|phenyl) |butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (c) 9 ooo -Z MI

M. - I - 6( 2 65 2-/УЬ M. ro 0-47 TM Ts 0-4 7M7 My more 7 more eighth ve 7 what else

In a vial with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (164.3 mg, 0.4372 mmol) and carbonyl diimidazole (77.70 mg, 0.4792 mmol) were combined in tetrahydrofuran (2.576 mL) and stirred for 120 min at 50 "C with the lid open. Then tert-butyl 2,2-dimethyl-4-| 4-(4-sulfamoylphenyl)butyl|pyrrolidine-1-carboxylate (179.5 mg, 0.4372 mmol) in tetrahydrofuran (3.436 mL), followed by 1,8-diazabicyclo/5.4.0)undec-7-ene ( 137.0 mg, 134.6 μl, 0.9002 mmol) and the reaction was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline. The organic layer was dried over sodium sulfate, evaporated, then purified using the reversed-phase HPLC-MS method, using a column Ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (rp: 00C-4252 - О0О-АХ) and a double gradient from 30-99 95 of mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, volume injection container - 950 μl and column temperature - 25:70). Fractions of the target product were combined and acetonitrile was removed under reduced pressure.

Then the material was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1X) and saline solution (1X), dried (sodium sulfate), filtered and concentrated to obtain tert-butyl-4-I4-(4-(2-chloro-6-( 3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|phenyl|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (132.8 mg, 40 95 ), clear oil. MO-IER ip/2 calcd. 767.27313, found 768.2 (M.-1)k; Retention time: 0.96 min. (Method RH A).

Stage 4: 2-chloro-M-I4-(4-(5,5-dimethylpyrrolidin-3-yl/butylIphenyl|sulfonyl-b-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1- il|Ipyridine-3-carboxamide o oo Ya. chu

N | N o- t M s o- M7 s in VosM in NM

Tert-butyl 4-I4-(4-Ce-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|phenyl|butyl|- 2,2-dimethylpyrrolidine-1-carboxylate (132.8 mg, 0.1729 mmol) was dissolved in dichloromethane (579.5 μL) and trifluoroacetic acid (904.5 mg, 611.1 μL, 7.933 mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The organic layer (sodium sulfate) was dried, filtered, and concentrated to a white solid, 2-chloro-M-I(4 -(4-(5,5- dimethylpyrrolidin-3-yl/butyl|Iphenyl|Isulfonyl-b-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide ( 99.8 mg, 86 95).MSO-IER t/72 calcd 667.2207, found 668.3 (M'-1)k Retention time: 0.66 min (RC Method A).

Stage 5: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|17.2 .2.111,14.05,10|hetracose-1(21),5,7,9,19, 22-hexane-2,2,4-trione (Compound 52) t oo o oo

N | N ve nm c

To the solution // 2-chloro-M-I4-(4-(5,5-dimethylpyrrolidin-3-yl)butyl|Ifenyl|sulfonyl-6-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy| Potassium carbonate (103.2 mg, 0.7470 mmol), cesium fluoride (27.24 mg , 0.1793 mmol) and a small amount of molecular sieves Z A. The resulting mixture was stoppered and heated to 155 "C overnight. It was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried (sodium sulfate) , filtered and concentrated to an orange oil, which was purified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 100 956 ethyl acetate to give 12,12-dimethyl-8-(3-12-|(1-(trifluoromethyl)cyclopropyl| ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|17.2.2.111,14.05,10|tetracose-1(21),5,7,9,19,22 -hexane-2,2,4-trione (compound 51) (25 mg, 26 95) as a white solid p urea 1H NMR (400 MHz, DMSO-46) 5 12.21 (5, 1H), 8.17

Zo (a, 9 - 2.8 Hz, 1H), 8.07 (a, U - 7.8 Hz, 1H), 7.86 (a, 9 - 8.3 Hu, 1), 7.76 (a, U - 8.0 Hu, 1H), 7.46 ( y, 9 - 16.6 Hz, 2H), 6.89 (a, U - 8.3 Hz, 1H), 6.10 (a, 9 - 2.8 Hz, 1H), 4.31 (I, 9 - 7.0 Gu, 2H), 2.92 - 2.80 ( t, 1H), 2.74 (a, U - 13.9, 6.9 Hz, 1H), 2.19 (5, 1H), 2.07 (U 2 7.1 Hu, 2H), 1.94 - 1.85 (t, 2H), 1.80 (5, 1H ), 1.70 (yes, U - 11.7, 5.3 Hz, 1H), 1.60 - 1.52 (t, 1H), 1.49 (5, 6H), 1.44 - 1.34 (t, 2H), 1.02 (actions,

U - 12.8, 6.7 Hz, 1H), 0.98 - 0.93 (t, 2H), 0.89 (a, U - 10.8 Hz, 2H), 0.77 (d, U - 11.6 Gu, 1H), 0.36 (5, 1H). MO-IER t/» calc. 631.244, found 632.1 (М--1)хк; Holding time: 2.46 min. (Method of RH B).

Stage 6: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|17.2 .2.111,14.05,10|hetracose-1(21),5,7,9,19, 22-hexane-2,2,4-trione (enantiomer 1) (compound 54) and 12,12-dimethyl-8- (3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11-triazatetracyclo|17.2.2.111,14.05,10|hetracose-1 (21),5,7,9,19,22- hexane-2,2,4-trione (enantiomer 2) (compound 55) and you o o o o o o a zizyu zim o vro, -- o o o o, I o o ono, v a v a v ta epapioteg 1 epapioteg 2

Racemic 12,12-dimethyl-8-(3-12-(1--trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11-triazatetracyclo|1 7.2. 2.111,14.05,10|tetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (21.9 mg, 0.03411 mmol) was subjected to chiral resolution using NKR-

chromatography using Spiga!Rak AB-N (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 2595 acetonitrile/methanol (90:10)/75 95 carbon dioxide at 10 ml/min for 6.0 min (vol. injection volume - 70 μl of a 24 mg/ml solution in a mixture of 8595 acetonitrile/methanol (90:10)/15 95 dimethylsulfoxide) with obtaining as the first eluted enantiomer 12,12-dimethyl-8-(3-12-11-« trifluoromethyl)cyclopropyl|vethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11-triazatetracyclo|17.2.2.111,14.05,10|hetracose-1(21),5,7,9, 19,22-hexane-2,2,4-trione (enantiomer 1) (compound 54) (10.01 mg, 92 95) as a white solid;

MO-ER it/2 calc. 631.244, found 632.2 (M--1)x; Retention time: 2.44 min (LC method B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl) -2A6-thia-3,9,11-triazatetracyclo!|17.2.2.111,14.05,10|tetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione. (enantiomer 2) (compound 55) (8.59 mg, 80 95) as a white solid; 1H NMR (400 MHz, DMSO-ab) b 12.20 (5, 1H), 8.17 (0, 9 - 2.8 Hz, 1H), 68.07 (ai, 9 - 8.0, 2.1 Hz, 1n), 7.86 (j, 9 - 8.3 Hz, 1H), 7.76 (aa, y - 8.1, 2.0 Hu, 1H), 7.49 (y, 9 - 8.2 Hu, 1H), 7.44 (a, - 8.2 Hz, 1H), 6.90 (y, U - 8.3 Hu, 1H), 6.10 (a, 9 - 2.7 Hz, 1H), 4.31 (I, U 2 7.0 Hu, 2H), 2.87 (y, U - 13.4, 6.4 Hz, 1H), 2.74 (a, 9 - 14.0 , 7.0

Hu, 1H), 2.19 (Y, U - 10.4 Hu, 1H), 2.07 (Y, U - 7.1 Hu, 2H), 1.89 (ai, U - 13.4, 6.0 Hz, 2H), 1.80 (a, 9 - 8.4 Gu, 1H), 1.70 (yes, U - 11.6, 5.4 Hz, 1H), 1.55 (4, U - 14.0, 7.0 Hz, 1H), 1.49 (5, 6H), 1.39 (1.9 - 12.3 Hz, 2H ), 1.02 (a, U - 12.6, 6.5 Gu, 1H), 0.96 (14, U - 4.9, 4.4, 3.1 Hz, 2H), 0.91 - 0.85 (t, 2H), 0.77 (a, U - 10.7 Hz, 1H), 0.36 (5, 1H), MO-IER t/2 calc. 631.244, found 632.2 (Ma1)k; Holding time: 2.44 min. (Method of RH B).

Example 15: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo |17.3.1.111,14.05,1O|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 56) and 12,12 -dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|17.3.1.111,14.05 ,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 57)

ИЙ du ИЙ du | dur o--4 CMT tm 0-2 o--4 CMT tm t 0-2 Tm ek ek ek epapboteg 1 epapboteg 2

Stage 1: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

Zo (enantiomer 1) (Compound 56) and 12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3 ,9,11-triazatetracyclo|17.3.1.111,14.05,1O|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 57) 9 was 0 oo b oo v v v epapioteg 1 epapioteg 2

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11-triazatetracyclo|1 7.3 .1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (41.7 mg, 0.06575 mmol) was subjected to chiral separation by means of NKR chromatography using SpigaiaRak A5-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 2595 acetonitrile/methanol (90:10)/75 95 carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl of a 24 mg/ml solution in 85 95 acetonitrile/methanol (90:10)/15 96 dimethylsulfoxide) with obtaining 12,12-dimethyl-8-(3-12-1P1) as the first eluted enantiomer -(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11-triazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(22),5,7 ,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (compound 56) (20.2 mg, 97,965); MSO-IER t/z calc. 631.244, found 632.2 (Ma) Kk;

Retention time: 2.44 min. yl)-2A6-thia-3,9,11-triazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2, 4-trione (enantiomer 2) (compound 57) (15.9 mg, 75 95); IN NMR (400 MHz, DMSO-ab) 5 12.44 (5, 1H), 8.21 (a,

U 2.68 Hz, 1H), 7.87 - 7.75 (t, ZN), 7.63 - 7.57 (t, 2H), 6.93 (ai, U - 68.2, 1.2 Hz, 1H), 6.12 (aa, U - 2.8, 0.9 Hz, 1H), 4.31 (Y, U - 7.0 Gu, 2H), 2.75 (a, 9 - 6.0 Hz, 2H), 2.68 - 2.62 (t, 1H), 2.11 - 2.05 (t,

ЗН), 1.83 (а, У - 12.6, 6.3 Гу, 2Н), 1.58 (5, ЗН), 1.51 (5, 6Н), 1.15, 9 - 8.9 Hz, 1Н), 0.97 (а, 9 - 3.4

Hu, 1H), 0.97 - 0.95 (t, 2H), 0.91 (5, 1H), 0.90 (5, 2H), 0.72 (5, 1H). MO-IER t/:2 calc. 631.244, found 632.2 (M--1)k; Retention time: 2.43 min (method RH B).

Example 16: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,20 ,25-pentaazatetracyclo|19.3.1.111,14.05,10|hexacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 1) (Compound 63) and 12,12-dimethyl-8-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,20,25- pentaazatetracyclo |19.3.1.111,14.05,10|)hexacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 2) (Compound 64) o Log hgo MO o Bivr 1 o ku Bier2 vo. ron VivrZ 92 Bivr4

Ч-3к У-- --- 6 Ю ЕЮ. ОБ --З2З703073--- (o) o o (6) (o)

NM O vivr5 NM OH verb vom OH Zivr7

Ov di shi nochi I-2pcs7

Fe

Vosm OM5 viverv Vosm MN on? Gu Vivre no di schu y Go -- t oo y

Y o) on i i s on Y B

M, mm Bivr 10 m ss Go Vivr 11

I ZU o to o oo and M and Z Z.

Ф и МВ и МВ вс 7 в эр и клнс ше ла нс epapioteg 1 epapboteg2

Stage 1: ethyl-1-(bromomethyl)-2-oxocyclohexanecarboxylate

A solution of /-ethyl-2-cyclohexanone carboxylate (84.0 g, 493 mmol) was added dropwise to a suspension of 60 90 sodium hydride (25.7 g, 641 mmol) and hexamethylphosphoramide (112 ml, 641 mmol) in tetrahydrofuran (850 ml). in tetrahydrofuran (350 mL) for four hours, and the resulting mixture was stirred at room temperature for one hour. Then, dibromomethane (173 mL, 2470 mmol) was added dropwise over one hour, and the mixture was heated under reflux at 70 "C for 16 hours. The reaction mixture was diluted with diethyl ether (6 L), the organic layer was washed with water (5 x 850 mL), the aqueous phases were discarded, and the organic phase was dried over sodium sulfate and concentrated. as a clear oil. Purity was determined to be ca. 80 95 by IN NMR. 1H NMR (250 MHz, SOSIS) 5 4.35-4.15 (t, 2H), 3.88- 3.50 (ad, 2H), 2.75-2.64 (da, 1H ), 2.49-2.41 (t, 2H), 2.30-2.17 (p, 2H), 2.10-1.75 (t, 2H), 1.74-1.53 (t, 2H), 1.32-1.22 (t, ЗН). The crude substance was used at the next stage without additional purification.

Stage 2: diethyl-2-methyleneheptandisoate

Wow, ok, wow. ovi ov (c) (o)

A suspension of ethyl 1-(bromomethyl)-2-oxocyclohexanecarboxylate (68 g, 258 mmol) and potassium carbonate (71.4 g, 517 mmol) in ethanol (600 mL) was stirred for 16 hours at room temperature. The resulting mixture was filtered, the solids were discarded, and the filtrate was concentrated and purified by chromatography on silica gel using a gradient of 0-15 95

From hexane/ethyl acetate to give diethyl 2-methyleneheptandisate (45.2 g, 77 9Uo) as a clear oil. YAN NMR (250 MHz, SOSIZ) 6 6.17 (v, 1H), 5.54 (5, 1H), 4.23-4.06 (t, 4H), 2.35-2.15 (i, 4H),

1.73-1.40 (t, 4H), 1.29-1.07 (t, 6H). MO-IER t/2 calc. 228.29, found 229.0 (Ma-1)k. Holding time: 4.97 min. (Method РХ 0).

Stage 3: diethyl 2 (2-methyl-2-nitropropyl)heptanedioate

MO»2 kyu. ry rovi 86-22 that (c) (c) o o

A mixture of diethyl 2-methyleneheptanedioate (48.6 g, 213 mmol), 2-nitropropane (58 mL, 639 mmol), and 1,8-diazabicyclo[5.4.O)undec-7-ene (3.2 mL, 21 mmol) ) was heated at 85 "C for five hours.

The mixture was concentrated and purified by silica gel chromatography using a gradient of 0-15 95 hexane/ethyl acetate to give diethyl 2-(2-methyl-2-nitropropyl)heptanedioate (58 g, 85 95) as a clear oil. MO-IER t/2 calc. 317.38, found 318.1 (М--1)хк. Holding time: 5.19 min. (Method РХ 0).

Stage 4: Ethyl 5-(5,5-dimethyl-2-oxopyrrolidin-3-yl)pentanoate

MO" (e) (c) what --- li in (c) (c)

To a solution of diethyl-2(2-methyl-2-nitropropyl)heptanedioate (19 g, 59.8 mmol) in ethanol (400 ml) was added a suspension of nickel Raney (9 g) and the resulting mixture was heated to 80 "C for 22 hours in in a Parr reactor under a hydrogen pressure of 2 bar. Celite (50 g) was added to the reactor and the mixture was filtered. The solids were discarded and the filtrate was concentrated in vacuo to give ethyl 5-(5,5-dimethyl-2-oxopyrrolidin-3-yl)pentanoate (13.2 g, yield 91 95) as a pale oil.

MO-IER t/2 calc. 241.33, found 242.1 (Ma-1)w. Holding time: 3.79 min. (The method of RH O).

The crude product was used for the next step without further purification.

Stage 5: 5-(5,5-dimethylpyrrolidin-3-yl)upentan-1-ol (c)

NM about NM on

Oh yes

Lithium aluminum hydride (6.2 g, 164, 1 mmol), then the resulting suspension was heated under reflux in a nitrogen atmosphere for 17 hours. The mixture was carefully quenched with a saturated aqueous solution of sodium sulfate (50 mL) and filtered. The solids were removed, and the aqueous phase was separated and discarded. The organic phase was concentrated to obtain 5-(5,5-dimethylpyrrolidin-3-yl)upentan-1-ol (8.8 g) as a pale yellow oil. MO-IER t/2 calc. 185.31, found 186.3 (M--1)w. Holding time: 1.98 min. (Method РХ 0). The crude product was used for the next step without additional

From cleaning.

Stage 6: tert-butyl 4-(5-hydroxypentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

A solution of sodium bicarbonate (24.5 g, 291.4 mmol) in water (150 mL) followed by the addition of di-tert-butyldicarbonate (31.8 g, 145.7 mmol). The obtained heterogeneous mixture was stirred at room temperature for two hours. The phases were separated and the aqueous phase was discarded. The organic phase was concentrated in vacuo and purified by chromatography on silica gel, using a gradient of 0-4595 hexanes/(ethyl acetate, to obtain tert-butyl 4-(5-hydroxypentyl)-2,2-dimethylpyrrolidine-1-carboxylate (32.0 g, 77 905) in the form of a transparent oil. 1H

NMR (250 MHz, SOSIZ) 5 4.29 (d, 1H), 3.53 (5, 1H), 3.37 (d, 2H), 2.75 (d, 1H), 2.05 (5, 2H), 1.87 (t, 1H), 1.43-1.17 (t, 23H). MO-IER t/: calc. 285.43, found 286.4 (M--1) w. Holding time: 5.20 min. (Method РХ 0).

Stage 7: tert-butyl 2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate ut bo-t-Vu Sh

A solution of tert-butyl-4-(5-hydroxypentyl)-2,2-dimethylpyrrolidine-1-carboxylate (10.5 g, 36.8 mmol) and triethylamine (10.3 mL, 73.6 mmol) in dichloromethane (100 ml) was cooled in an ice water bath. Methanesulfonyl chloride (3.2 mL, 40.5 mmol) was then added dropwise over 15 minutes, and the resulting mixture was stirred for one hour in an ice bath.

The reaction was quenched with saturated sodium bicarbonate solution (50 ml). The aqueous phase was discarded, and the organic phase was concentrated to obtain tert-butyl-2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate (13.3 g, 99 95) as a yellow oil. Mo-

IER t/7 calc. 363.16, found 364.3 (M'-1)-. Holding time: 5.77 min. The crude product was used in the next stage without additional purification (method РХ 0).

Stage 8: tert-butyl 4-(5-aminopentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Wu What " Wu Sh

A solution of tert-butyl-2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate (13.3 g, 36.6 mmol) in tetrahydrofuran (275 mL) and 28 95 aqueous ammonium hydroxide (275 mL ) was stirred at 50 "C for 24 hours. Tetrahydrofuran and ammonia were removed under vacuum, and the remaining aqueous phase was extracted with dichloromethane (3 x 100 ml), the combined organic layers were concentrated to an oil and purified by chromatography on silica gel using a gradient of 0 -1595 dichloromethane/methanol (0.25 95 ammonium hydroxide) to give tert-butyl-4-(5-aminopentyl)-2,2-dimethylpyrrolidine-1-carboxylate (5.4 g, 52 95) as a pale oil. YAN NMR (250 MHz, SOSIZ) 6 3.53 (d, 1H), 2.75 (d, 1H), 2.05 (5, 2H), 1.86 (t, 1H), 1.43-1.10 (t, 23H). MO-IER t /2 calcd 284.45, found 285.4 (M--1) gk Retention time: 4.07 min (Method РХ 0).

Stage 9: tert-butyl 2,2-dimethyl-4-(5-((b-sulfamoyl-2-pyridyl)amino|pentyl|pyrrolidine-1-carboxylate)

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ZU on? n i

M. 2 and the same

Tert-butyl-4-(5-aminopentyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.028 g, 3.614 mmol), b6-fluoropyridine-2-sulfonamide (636 mg, 3.610 mmol) were charged into a 100 ml round-bottomed flask. and anhydrous dimethyl sulfoxide (10 mL). Potassium carbonate (519 mg, 3.755 mmol) (ground in a mortar) was added and the mixture was stirred at 100 C for 20 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 ml) and poured into saturated aq

A solution of ammonium chloride (50 ml). The two phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL), and the combined extracts were washed with brine (40 mL). After drying over sodium sulfate and evaporation, the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100 95 over 30 minutes) in hexane. The pure fractions were collected and the solvents evaporated to give tert-butyl-2,2-dimethyl-4-(5-((6b-sulfamoyl-2-pyridyl)amino|pentyl|pyrrolidine-1-carboxylate) (1.184 g, 74 95) in in the form of a solid white foam. MO-

IER tp/2 calc. 440.24573, found 441.3 (M.-1)k; Holding time: 1.86 min. (Method of RH B).

Stage 10: tert-butyl 4-(5-C(6-Ce-chloro-6-I3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridylamino|pentyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Y B o du o-y M M SI x --63 Mk M si Sq. ne z ro 7 oo mn pe AH ALY

In a bottle with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (19.8 mg, 0.8511 mmol) and carbonyl diimidazole (138.0 mg, 0.8511 mmol) were combined in tetrahydrofuran (3.588 mL) and stirred for 120 min at 50 "C with the lid open. Then tert-butyl-2,2-dimethyl-4- (5-((6b-sulfamoyl-2-

pyridyl)amino|IpentylIpyrrolidine-1-carboxylate (250 mg, 0.5674 mmol) in tetrahydrofuran (4.785 mL) followed by the addition of 1,8-diazabicyclo|5.4.F)undec-7-ene (169.7 μL, 1.135 mmol) ) and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using shallow gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 4-I15-(6-C2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine) -3-carbonyl|sulfamoyl|-2- pyridylyamino|Ipentyl|-2,2-dimethylpyrrolidine-1-carboxylate (416.8 mg, 92,965). MO-IER t/2 calcd 197.2949, found 798.3 (M--1) k Retention time: 0.92 min (method RH A).

Stage 11: 2-chloro-M-I((6-(5-(5,5-dimethylpyrrolidin-3-yl)pentylamino|-2-pyridyl|sulfonyl|/-6-

3-(2-P1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide

M. 2 May 07333330 M. 2 M. 2 o-4 MM s o-4 MTMO s i oo ooo

Tert-butyl 4-15-C6-C2-chloro-6-I3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino|pentyl |-2,2-dimethylpyrrolidine-1-carboxylate (416.8 mg, 0.5221 mmol) was dissolved in dichloromethane (1.189 mL) and trifluoroacetic acid (1.845 mL, 23.95 mmol) was added to the mixture and the mixture was stirred at room temperature within 60 min. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The organic layer was dried (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-M-I(6-(5-(5,5- dimethylpyrrolidine-3-ylopentylamino|-2-pyridylIsulfonyl|-6-(3 -(2-1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (361 mg, 91 95). MO-IER t/72 calc. 697.2425, found 698.2 (M Retention time: 0.64 min (Method RH A).

Stage 12: 12,12-dimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,20, 25-pentaazatetracyclo|19.3.1.111,14.05,10|hexacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 1) (Compound 63) and 12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,20,25- pentaazatetracyclo |19.3.1.111,14.05,10)hexacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 2) (Compound 64)

Y chu 8 9 o cho y M to -5 -8 el da ona Vo zo epapioteg 1 epapioteg 2

To a solution of 2-chloro-M-((6-(5-(5,5-dimethylpyrrolidine-3-ylopentylamino|-2-pyridyl|sulfonyl|-6-

Potassium carbonate (392.6 mg) was added to 3-(2-P1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (361 mg, 0.4736 mmol) in dimethylsulfoxide (13.22 mL) . saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 422 mg of a reddish-brown amorphous solid, which was subjected to chiral separation by means of NCR chromatography using GSC 3 (column 250 x 21 mm, size particles of 5 μm) with a mobile phase of 60 95 methanol (20 mM additive MNH))/40 95 carbon dioxide at 30 ml/min, with obtaining as the first eluted enantiomer 12,12-dimethyl-8-(3-12-(1 -"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,20,25- pentaazatetracyclo|19.3.1.111, 14.05,10|)hexacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 1) (compound 63) (74.4 mg, 47 95 ) in the form of a white solid; 1H NMR (400 MHz, dmeoo-avb) b 12.69 (p5, 1H), 8.19 (a, U 5 2.7 Hz, 1H), 7.78 (a, U - 8.2 Hz, 1H), 7.48 (5, 1H), 7.08 (a, 9 - 6.9 Hz, 2H), 6.85 (a, U - 8.0 Gu, 1H), 6.58 (5, 1H), 6.07 (a, U - 2.6 Hz, 1H), 4.31 (Her, U) - 7.0 Hz, 2H), 3.84 (a, 9 - 14.2 Hu, 1H), 3.06 (5, 1H), 2.89 (5, 1H), 2.79 (5, 1H), 2.08 (I, U - 7.1 Hu, ЗН), 1.81 (а, У - 11.6, 5.4 Hz, 1Н), 1.60 (а, У - 9.1 Hz, 1Н), 1.55 (а, У - 6.2 Hz, 6Н), 1.47 (y, У - 12.5 Hz, ЗН), 1.27 (Od, 9 - 26.3 Hz, ZN), 1.01 (5, 1H), 0.98 - 0.93 (t, 2H), 0.93 - 0.84 (t, ZN), MO-IER ip/2 calc. 661.2658, found 662.2 (М-а-1)ж; Retention time: 2.29 min. -2A6- thia-3,9,11,20,25-pentaazatetracyclo|19.3.1.111,14.05,1O|hexacose-1(24),5,7,9,21(25),22-hexane-2,2 ,4-trione (enantiomer 2) (compound 64) (79.2 mg, 50 95) as a white solid; 1H NMR (400 MHz, DMSO-ab) b 12.50 (5, 1H), 8.21 (a, 9U - 2.8 Hz, 1H), 7.82 (0, 9 - 8.2 Hz, 1H), 7.56 (5, 1H), 7.14 (5, 1H), 6.91 (a, 9 - 7.8 Hz, 2H), 6.70 (5, 1H), 6.11 (5, 1H), 4.31 (her, U - 7.0 Hz, 2H), 3.88 (5, 1H) . 1H), 1.67 - 1.57 (t, 1H), 1.55 (y, U - 10.5 Hz, 6H), 1.48 (I, U - 12.1 Hz, ЗН), 1.30 (5, 2H), 1.23 (5, 1H), 1.01 (a, 9 - 9.5 Gu, 1H), 0.98 - 0.95 (t, 2H), 0.95 - 0.87 (t, ZN), MO-IER t/: cal. 661.2658, found 662.2 (M--1) flat; Holding time: 2.29 min. (Method of RH B).

Example 17: Preparation of (145)-8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 66) (o) oo r o n m/8- s NM us 2 vier 1 ma i m se ier 2 - 652 i m ke shi

VosmM MN o shchi o

AHA uk

In o o, ro) o o, Mo

M. - M / M. s4 M // o-2 MOTO si x vir Z 0-7 M M s U Vier4

S a NK Tu S sho NM - 6-2 (o)

Mind NM

Jo "TEA o 0, ye5 m? Sai mm M s me 0-7 M more schools,

Stage 1: tert-butyl (45)-2,2-dimethyl-4-3-(6b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-15 1-carboxylate

Fo Fe nar nau"

M. 2 Has

Racemic tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (7 g, 16.97 mmol) was subjected to chiral separation using NKR chromatography using SpPigaiRak IS (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 40 95 methanol/b0 95 carbon dioxide at 70 ml/min for 11.0 min (injection volume - 500 μl of a solution of 32 mg /ml in methanol), giving the first elution peak, tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (3 ,4481 g, 99,965). MO-IER ip/2 calc. 412.21442, found 413.2 (M.-1)x; Holding time: 0.63 min. (Method of RH A).

Stage 2: tert-butyl (45)-4-3-C(6-C2-chloro-6-13-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate r o bo,

NM sht zkh r - M. 2 o-th IOM oi U o d) AT t - y,

M (o) uat t U Na (9)

Part A: To 2-chloro-6-N3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (8.9 g, 24.60 mmol) in tetrahydrofuran (80 mL) was slowly added carbonyldiimidazole (4.4 g, 27.14 mmol). The mixture was stirred at ambient temperature for 1 hour.

Part B. To tert-butyl (45)-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (10.1 g, 24.48 mmol ) in tetrahydrofuran (40 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido|(1,2-afiazepine (11.0 mL, 73.56 mmol), then the activated ester from Part A and the mixture was stirred at ambient temperature for 16 h. The reaction was quenched with 50 mL of water and most of the tetrahydrofuran was removed in vacuo. The remaining mixture was diluted with water (250 mL) containing hydrochloric acid (26 mL of 6 M, 156.0 mmol ), and acidified to pH - 2-3. The transparent dark yellow solution was extracted with ethyl acetate (400 ml). The organic phase was washed with 300 ml of saline solution, dried over magnesium sulfate, filtered and concentrated in vacuo, obtaining a thick yellow oil. The crude reaction the mixture was chromatographed on a C18 4159 reversed-phase column, eluting with a mixture of 50-100 95 water/acetonitrile to obtain tert-butyl (45)-4-I3-KC6-Ce-chloro-6-I3-(3,3-dicyclopropylpropox i)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (11.2 g, 60 95). MO-IER tp/2 calc. 755.3232, 756.3 (M.-1) found; Holding time: 2.53 min. (Method of RH B).

Stage C: 2-chloro-6-3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-I((6-(3-((35)-5,5-dimethylpyrrolidin-3-yl) propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetic acid salt) o o, l o o, l

ZM i ZYM ex

Gee! ie more, (o! mon more, /y /y yes NM " ha NM (o)

Um nm zho PLEA

To tert-butyl (45)-4-I3-(6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino| To ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (16.7 g, 22.08 mmol) in dichloromethane (80 mL) and toluene (40 mL) was added trifluoroacetic acid (10 mL, 129.8 mmol) and the mixture was stirred at ambient temperature for 22 h. The solvent was removed on a rotary evaporator at 35 "C, obtaining a thick oil of yellow

From the color The oil was diluted with dichloromethane (80 mL) and toluene (120 mL), and the solvent was removed by rotary evaporation at 55 °C. The process was repeated with dichloromethane and toluene to give 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazole-1 -yl|-M-((6-(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetate salt)) (22.6 g, 133 95, the product is contaminated with residual toluene and trifluoroacetic acid) in the form of a thick oil. "IN NMR (400 MHz, DMSO-46) b 12.73 (5, 1H), 8.60 (5, 2H), 8.39 (

У -2.9 Hz, 1Н), 8.11 (а, У - 8.3 Hz, 1Н), 7.71 (а, У - 8.4 Hz, 1Н), 7.63 (ai, у - 8.5, 7.2 Hz, 1Н), 7.26 - 7.22 ( t, 1H), 6.75 (ai, y - 8.5, 0.7 Hz, 1H), 6.20 (j, U - 2.9 Hz, 1H), 4.40 (I, U - 6.8 Hz, 2H), 3.36 (ad,

U same 12.0, 5.3 Hu, 1H), 3.24 (peri, U - 6.7 Hz, 2H), 2.80 (Id, U - 11.6, 10.8, 6.1 Hu, 1H), 2.41 - 2.32 (t, 1H), 2.02 - 1.85 (t, ЗН), 1.61 - 1.28 (t, 8Н), 1.24 (а, 7 - 6.2 Gu, 4Н), 0.69 (di, У - 8.3, 5.0 Hz, 2Н), 0.49 - 0.34 (t, ЗН), 0.34 - 0.25 (t, 1H), 0.25 - 0.14 (t, 2H), 0.11 - 0.00 (t, 2H). MO-IER t/ calc. 655.27075, found 656.3 (M'-1) k; Holding time: 1.71 min. (Method of RH B).

Stage 4: (145)-8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 66)

ti o, l t m sh- o yur,

M (| nn M; and I about M, pa v ie d- and v nyk about Kun

NM in "TEA

To the solution 2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-((6-I3-((35)-5,5- dimethylpyrrolidin-3-yl|propylamino| -2-pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetate salt) (17.5 g, 22.72 mmol) in MMP (300 mL) was added potassium carbonate (15.3 g, 110.7 mmol), and then cesium fluoride (3.8 g, 25.02 mmol) The mixture was purged with nitrogen for 5 min.

The mixture was heated at 150 °C for 20 hours. The reaction mixture was cooled to room temperature, added to water (1200 mL) (a 5-liter flask cooled in an ice bath was used) and acidified by careful addition of hydrochloric acid (20 mL of 6 M, 120, 0 mmol), followed by solid citric acid (45 g, 234.2 mmol). The mixture was stirred in an ice bath for 1 h. The solid was collected by filtration using a medium frit (slow filtration), the wet precipitate on the filter was dissolved in ethyl acetate (1000 mL) and washed with 500 mL of brine. The aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered through celite, and concentrated in vacuo to give a pale yellow foam. The crude product was diluted with acetonitrile, divided into three equal volumes (15 mL ) and chromatographed on a reversed-phase C18 4159 column, eluting with a mixture of 50-100 95 acetonitrile/water to obtain (145)-8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12, 12-dimethyl-2Ab6-thia-3, 9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|hetracose-1(22),5,7,9,19 (23),20-hexane-2,2,4-trione (Compound 66) (8.91 g, 63 95). "IN NMR (400 MHz, DMSO-ab) b 12.48 (5, 1H), 8.20 (49.9 - 3.2 Hz, 1H), 7.81 (y, U - 8.0 Hu, 1H), 7.57 (I, U - 7.8 Hz, 1H), 7.05 (a, y - 7.0 Hz, 1H), 6.97 (5, 2H), 6.71 (a, U - 8.4 Gu, 1H), 6.10 (a, U - 3.2 Hz, 1H), 4.37 ( I, 9 - 6.7 Hz, 2H), 3.91 (5, 1H), 3.15 (5, 1H), 2.95 (y, U - 13.3 Gu, 1H), 2.71 (5, 1H), 2.12 (5, 1H), 1.95 - 1.71 (t, 4H), 1.60 (y, U - 3.3

Hu, 6H), 1.51 (5, ЗН), 1.39 - 1.25 (t, 1H), 0.67 (a, 9 - 8.5, 4.1 Hz, 2H), 0.47 - 0.33 (t, 4H), 0.30 (I, U - 8.0 Hz, 1H), 0.20 (aa, 9 - 9.7, 4.4 Hz, 2H), 0.04 (a, U - 8.3 Hz, 2H). MO-IER t/: calc. 619.29407, found 620.3 (M--1) w; Holding time: 10.3 min. (Method RH B).

Example 18: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18 ,20-pentaazatetracyclo|17.2.2.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 72) and 12,12-dimethyl-8-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,20- pentaazatetracyclo !|17.2.2.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

Zo (enantiomer 2) (Compound 73) oo

A. la

Eighth MNN va in Vier1 Shchi A se Verg hu a Iva o o- My o

VosM at 9 o'clock

B: "V pav: d. gu r Zivrz about you; t Zivr4 v - TT, v - t,

VosM NM 2 to ge "ZhK A o- M cm M mn 0-5 M ru u o i Uk s to code v v epapiyoteg 1 epapiyoteg 2

Stage 1: tert-butyl 2,2-dimethyl-4-3-K5-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate duo 7 xx

VosM chu t" fi lono tu. PO 00 - -

M SI no

To tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (400 mg, 1.560 mmol) and b-chloropyridine-3-sulfonamide (300.5 mg, 1.560 mmol) in dimethyl sulfoxide ( 3.368 ml) was added potassium carbonate (219.9 mg, 1.591 mmol) and the mixture was stirred at 1009 for 20 h. Then it was left to cool to room temperature. It was diluted with ethyl acetate and poured into saturated aqueous ammonium chloride. The layers were separated, then the organic layer was washed with brine, dried (sodium sulfate), filtered, and concentrated to a yellow foam which was purified by silica gel chromatography using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 2.2 - dimethyl-4-I3-(5-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (347 mg, 54 95) in the form of a white solid. MO-IER t/2 calc. 412.21442, found 413.2 (M--1); Holding time: 0.52 min. (Method of RH A).

Stage 2: tert-butyl 4-I3-(5-(C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o y 9 to mya motn Mem MY o MU mn 0-5 M' SI i ---2. 0-5 sich - sich

VosmM axis

In a vial with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (474.2 mg, 1.262 mmol) and carbonyl diimidazole (204.6 mg, 1.262 mmol) was combined in tetrahydrofuran (4.979 ml) and stirred for 120 min at 50 "C with the lid open. Then tert-butyl-2,2-dimethyl-4-I3-(5 -sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (347 mg, 0.8411 mmol) in tetrahydrofuran (6.642 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene ( 251.6 μl, 1.682 mmol) and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give pure product as well as mixed fractions. was searched using reversed-phase HPLC-MS using a Hypa C18 column (2) (75 x 30 mm, 5 µm particle size) commercially available

Rpepotepeh (art.: 00С-4252-00-АХ) and a double gradient of 30-99 95 mobile phase B during 15.0

From min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "С).

Pure fractions after preliminary purification with the reverse phase were combined and acetonitrile was removed by rotary evaporation. The residue was dissolved in ethyl acetate and washed with a small amount of saturated aqueous sodium bicarbonate, then dried (sodium sulfate), filtered and concentrated to a white solid, which was combined with the pure product from the silica gel column to give tert-butyl 4-I3-C5- C2-chloro-6-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine- -carboxylate (539.2 mg, 8395) as a white solid. MO-IER Ip/2 calcd. 769.2636, found 770.2 (M.-1); Retention time: 0.84 min. (RC method AND).

Step 3: 2-Chloro-M-(6-(3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-3-pyridyl|sulfonyl|-6-(3-(2-P-"trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide

Mom | M ss and o Mom | MU ss and A 0-7 -- - 0-7 no -- - where

VosM NM

tert-butyl 4-I3-C5-C2-chloro-6-I3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl |-2,2-Dimethylpyrrolidine-1-carboxylate (539.2 mg, 0.7000 mmol) was dissolved in dichloromethane (2.353 mL) and trifluoroacetic acid (2.474 mL, 32.11 mmol) was added to the mixture, and the mixture was stirred at room temperature. temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in a saturated aqueous solution of sodium bicarbonate and ethyl acetate and separated into layers (the solubility of the product in ethyl acetate under these conditions is low, the addition of a certain amount of methanol, necessary for evaporation of the organic layer without the use of a solid drying agent, helps). The organic layer was concentrated by rotary evaporation followed by vacuum drying, obtaining /2-chloro-M-I((6-I3-(5,5-dimethylpyrrolidin-3-yl)/upropylamino|-3-pyridyl|sulfonyl|-6- (3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide) (423.3 mg, 90 95) in the form of an off-white solid. MO-IER t/: calcd 669.2112, found 670.2 (MAT) k Retention time: 0.56 min (RH Method A).

Stage 4: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,20- pentaazatetracyclo|17.2.2.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 62) 7 oo 7 oo oo- t MU ss "mMsmno u o- tr ryu" in v nm

To the solution of 2-chloro-M-I|((6-(3-(5,5-dimethylpyrrolidin-3-yl)upropylamino|-Z-pyridyl|sulfonyl|-6-

Potassium carbonate (523, 523, 8 mg, 3.790 mmol), cesium fluoride (115.1 mg, 0.7577 mmol) and a small amount of molecular sieves Z A. The resulting mixture was closed and heated to 165 "C for 16 hours. The temperature was raised to 175 "C and mixed with h, then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried (sodium sulfate), filtered, and concentrated to 500 mg of a yellowish-brown amorphous solid, which was filtered and purified using the reversed-phase HPLC-MS method using a column I IPA C18 (2) (75 x 30 mm, size particles of 5 μm), which is sold

Rpepotepeh (рп: 000-4252-00-АХ), and a double gradient from 30-99 95 mobile phase B during

From 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 C) with obtaining 12, 12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,20-pentaazatetracyclo!|17.2. 2.111,14.05,10)tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 62) (24.2 mg, 6 95) in the form white solid. 1H NMR (400

MgGu, DMOO-ab) b 12.13 (5, 1H), 8.38 (5, 1H), 8.17 (y, 9U - 2.8 Hz, 1H), 7.91 - 7.64 (t, 2H), 7.42 (v, 1H), 6.63 (a, U - 8.8 Hz, 1H), 6.09 (y, 9 - 2.7 Hz, 1H), 4.30 (1, 9 - 7.1 Hz, 2H), 3.64 (5, 1H), 2.88 (5, 1H), 2.07 (9 - 7.1 Hu, ЗН), 2.03 - 1.92 (t, 2Н), 1.80 - 1.71 (t, 1Н), 1.54 (5, ЗН), 1.48 (5, ЗН), 1.38 (d, У - 13.8, 11.4 Hz, 4H), 0.98 - 0.92 (t, 2H), 0.92 - 0.85 (t, ЗН). MO-IER t/2 calc. 633.2345, found 634.2 (M.-1)k; Holding time: 2.03 min. (Method of RH B).

Stage 5: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,20- pentaazatetracyclo|17.2.2.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 12) and 12, 12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,20- pentaazatetracyclo!| 17.2.2.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 73)

io) oo o B in ? stupid xx

ССС --Ф M. uva: TA . that Jan a - code b v epapioteg 1 epapioteg 2

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18,20- pentaazatetracyclo!|17.2.2.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (17 mg, 0.02565 mmol) was subjected chiral separation by NKR chromatography using SpigaiRak A5B-N (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 1895 methanol (20 mM MNH additive)/82 95 carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl of a 24 mg/ml solution in a mixture of 90 95 methanol/10 95 dimethylsulfoxide with obtaining 12,12-dimethyl-8-(3-(2-P1-(trifluoromethyl)cyclopropyl) as the first eluted enantiomer) ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,20- pentaazatetracyclo!|17.2.2.111,14.05,10)tetracose-1(22),5,7,9 ,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (compound 72) (6.34 mg, 78 95) as a white solid; MO-IER t/: calc. 633.2345, found 634.4 (M.-1)j; Holding time: 2.08 min. (Method LC B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-12-11-"trifluoromethyl)cyclopropyl|vethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3, 9,11,18,20-pentaazatetracyclo|17.2.2.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2 ) (compound 73) (5.54 mg, 68,905) as a white solid. 1TH NMR (400 MHz, DMSO-ab) b 12.13 (5, 1H), 8.63 (5, 1H), 8.43 (5, 1H), 8.18 (y, 9 - 2.8 Hu, 1), 7.89 (a, U - 8.8 Hu, 1H), 7.85 (a, U - 8.4 Hu, 1H), 7.54 (5, 1H), 6.90 (ai, U - 8.3, 3.5 Hz, 1H), 6.67 (da, U - 9.0, 3.1 Hz, 1H), 6.11 (a, y - 2.8 Hu, 1H), 4.31 (I, U - 7.0 Hz, 2H), 3.66 (5, 1H), 2.90 (5, 1H), 2.08 (0, U 2 7.1 Hz, 2H), 1.92 (5, ZN), 1.77 (9, U - 12.5 Gu, 1H), 1.64 (a, U - 13.8

Hu, 1H), 1.55 (5, ЗН), 1.48 (5, ЗН), 1.46 - 1.34 (t, ЗН), 1.34 (5, 1Н), 0.97 - 0.94 (t, 2Н), 0.88 (5, 2Н) .

MO-ER t/2 calc. 633.2345, found 634.3 (M--1) k; Holding time: 2.08 min. (Method of RH B).

Example 19: Preparation of (145)-12,12-dimethyl-8-(3-(2-11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3 ,9,11-triazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 77) o he (c) he he he I vyvr1 to vyvr2 d- 5ier with spice vyvr4 oo IT o, ay; se willow

Vos-M 9 so i N yad, Zer5 i M. | 2 Va o-5 2 is) o-4 MTM oi rad z on - u sh Kk still o 0, 6 o, l de t 0-7 che s. here 0-4 more about vk a "in vk and vad 3: (35)-3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (c) one (c) Gen t

Racemic 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (100 g, 566.5 mmol) was separated by chiral NCR chromatography using a SpigaIRak AOB-H (column 2 x 25 cm) with a mobile

With a phase of 30 95 methanol/carbon dioxide at 60 ml/min (injection volume - 1 ml of a solution of 20 mg/ml in methanol to obtain the first eluted enantiomer (35)-3-(3-hydroxypropyl)-5,5-dimethyl -pyrrolidin-2-one (47 g, 48 95) as an off-white solid. TN NMR (400

MgHu, DMOO-ab) b 7.63 (5, 1H), 4.38 (1, U - 5.1 Hu, 1H), 3.39 (I, U - 5.6 Hz, 2H), 2.37 (da, 9 - 13.9, 9.6, 4.4 Hz , 1H), 2.02 (aa, U - 12.3, 8.6 Hz, 1H), 1.78 - 1.64 (t, 1H), 1.42 (Id, U - 12.8, 12.3, 8.4 Gu,

ЗН), 1.16 (ad, 9 - 17.9 Hz, 7Н). MO-IER t/2 calc. 171.12593, found 172.0 (Ma1)k; Holding time: 0.61 min. (Method of RH B).

Stage 2: 3-(35)-5,5-dimethylpyrrolidin-3-yl|propan-1-ol c) on on - - p» - - ' - E -yu»j- Yu-

A 5 L three-necked round-bottom flask was equipped with a mechanical stirrer, a heating hood, a dropping funnel, a 9-Ket temperature sensor/controller, and a nitrogen inlet/outlet. Lithium aluminum hydride granules (46.53 g, 1.226 mol) were loaded into the vessel under a nitrogen atmosphere. Then tetrahydrofuran (500 ml, 20 ml/g) was loaded into the vessel. Stirring was started and the temperature in the vessel was recorded at 20 °C. The mixture was left to stir at room temperature for 0.5 h to allow the granules to dissolve. The reactor temperature of the resulting gray slurry was 24 °C. A solution of (35)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (60 g, 350.4 mmol) in tetrahydrofuran (600 mL) was charged into the dropping funnel, and the clear pale yellow solution was added dropwise within 90 min. A little heating is required for dissolution. After completion of the addition, the temperature of the tank of the resulting grayish suspension was fixed at 24 "C. Then the mixture was heated to a boiler temperature of 65 "C and the conditions were maintained for 72 hours. Analysis of the reaction mixture at this point indicated that some residual starting material still remained and no change in product formation. Subsequently, the reaction was stopped at this stage. The heating jacket was removed and the vessel was equipped with a cooling bath. The suspension was cooled to 0 °C using a crushed ice/water cooling bath and then quenched by the very slow addition of water (46.53 mL) dropwise, followed by 15 wt. 96 sodium hydroxide solution (46.53 mL) and then water again (139.59 ml). The temperature of the obtained white suspension was 5 "C. The cooling bath was removed, and the vessel was again equipped with a heating jacket. The suspension was heated to 60 °C and kept for 30 min.

The warm suspension was filtered under vacuum through a Buchner funnel with a glass frit with a 25 mm celite layer. Then the sediment on the filter was washed by displacement with tetrahydrofuran at 60 C (2 x 350 ml) and then extracted for 30 min. The clear filtrate was concentrated under reduced pressure to give (55 g, 0.349 mol, yield 99 95) a clear light yellow viscous oil as the desired product, 3-((35)-5,5-dimethylpyrrolidine-3-yl|Ipropane -1-ol (55 g, 100 95). 1H

NMR (400 MHz, DMSO-ab) b 3.36 (I, 9 - 6.3 Hz, ZN), 2.95 (da, U - 10.6, 7.6 Hu, 1H), 2.40 (da, 9 - 10.6, 7.7 Hz, 1H), 2.12 - 1.97 (t, 1H), 1.69 (da, U - 12.1, 8.2 Gu, 1H), 1.47 - 1.25 (t, 5H), 1.08 (5,

ZN), 1.02 (5, ZN).

Zo Stage 3: tert-butyl (45)-4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylatone

Vos.

A three-neck round-bottom flask with a volume of 1 L was equipped with a mechanical stirrer, a cooling bath, a dropping funnel, a 9U-Ket temperature sensor, and a nitrogen inlet/outlet. 3-|((35)-5,5-dimethylpyrrolidin-3-yl|Ipropan-1-ol (25 g, 159.0 mmol) and dichloromethane (250 mL) were charged into the vessel under a nitrogen atmosphere, which gave a clear light yellow solution.

Stirring was started and the temperature in the vessel was recorded at 19 °C. Crushed ice/water was loaded into the cooling bath, and the temperature in the container was lowered to 0 °C. The dropping funnel was charged with triethylamine (22.16 mL, 159.0 mmol), which was then added neat dropwise over 5 minutes. No exotherm was observed. Then di-tert-butyl dicarbonate (31.32 g, 143.5 mmol) dissolved in dichloromethane (150 ml) was loaded into the dropping funnel. Then, a transparent, pale yellow solution was added dropwise for 30 minutes, which led to a gentle release of gas. No exotherm was observed. The cooling bath was removed and the resulting clear light yellow solution was allowed to warm to room temperature and stirring was continued at room temperature for 3 hours.

The reaction mixture was transferred to a separatory funnel and separated with water (75 ml). The organic layer was removed and washed with brine (75 mL), dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to give (45 g) a clear light yellow oil as the desired crude product. The material was purified by flash chromatography on a silica gel column (liquid loading with dichloromethane), eluting with a gradient from 10095 dichloromethane to 1095 methyl alcohol in dichloromethane over 60 minutes, collecting fractions of 50 ml. Fractions of the desired product were combined and concentrated under reduced pressure to obtain tert-butyl (45)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (39 g, 95 95). LN NMR (400 MHz,

DMSO-ab) b 4.35 (I, U - 5.2 Hz, 1H), 3.54 (y, U - 12.2, 6.3 Hz, 1H), 3.38 (i, U - 5.68 Hz, 2H), 2.76 (d, U - 10.2 Hz, 1Н), 1.47 (5, ЗН), 1.44 - 1.28 (t, 18Н), 1.24 (5, ЗН). MO-IER t/2 calc. 257.1991, found 258.1 (M--1)k; Holding time: 1.55 min. (Method of RH B).

Stage 4: tert-butyl (45)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate OM5

Vos. Vos. - - ryu

A three-necked 500 mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath, a dropping funnel, a .)-Ket temperature sensor, and a nitrogen inlet/outlet. Tert-butyl (45)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (25 g, 97.14 mmol) and dichloromethane (250 mL) were charged to the vessel under a nitrogen atmosphere, which gave a clear colorless solution. Stirring was started and the temperature in the vessel was recorded at 192C. A cooling bath was charged with crushed ice/water, and the vessel temperature was lowered to 0 °C. A dropping funnel was charged with triethylamine (17.60 mL, 126.3 mmol), which was added neat dropwise over 5 minutes. No exotherm was observed. .

A dropping funnel was then charged with methanesulfonyl chloride (8.277 mL, 106.9 mmol), which was added neat dropwise over 15 minutes, resulting in a light yellow suspension and an exothermic reaction up to 4°C. The mixture was continued to stir at 57°C for 1 h, when LC/MS analysis showed complete consumption of the starting material. The reaction mixture was further diluted with dichloromethane (200 mL) and then poured into saturated ammonium chloride solution (250 mL). The biphasic mixture was then transferred to a separatory funnel. The organic layer was removed, washed with saturated solution ammonium chloride (150 ml), dried over sodium sulfate (150 g) and then filtered through a Buchner funnel with a glass frit.

The filtrate was concentrated under reduced pressure to give tert-butyl (4S)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-II-carboxylate (29 g, 8995) as a clear amber oil. 1H NMR (400 MHz, DMSO-ab) 6 4.19 (I, Y - 6.4 Hz, 2H), 3.16 (5, ZH), 2.79 (a, Y - 10.2 Hz, 1H), 2.11 (5, 1H), 1.90 (19, U - 13.5, 6.0 Hz, 1H), 1.66 (give, 9 - 15.8, 7.6, 4.0 Hz, 2H), 1.51 - 1.22 (t, 20H). MO-IER t/72 calc. 335.17664, found 336.1 (M--1)w; Holding time: 1.74 min. (Method of RH B).

Stage 5: tert-butyl (45)-2,2-dimethyl-4-I3-(3-sulfamoylphenoxy)propyl|pyrrolidine-1-

Zo carboxylate 0, n m o o o, ? o as x, ;

Vos tok i NOM U U (F)

ON "in

3-Hydroxybenzenesulfonamide (750 mg, 4.331 mmol) and M,M-dimethylformamide (15 mL) were added to a 100 mL flask. Potassium carbonate (1.8 g, 13.02 mmol) and tert-butyl (45)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.5 g, 4.471 mmol) were added to the mixture ) at room temperature. The resulting mixture was stirred at room temperature for 48 hours, then heated to 50 "C for 5 hours. Then the mixture was poured into 1N citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a yellow oil which was purified by silica gel column chromatography (80 g column) using a gradient of 100 90 hexanes to 6595 ethyl acetate in hexane to give tert-butyl(45)-2,2-dimethyl-4-|3- (3-sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate (868 mg, 49 95) as a light yellow foam. 1H NMR (400 MHz, DMSO-ab) 5 7.47 (I, 9 - 8.0 Hu, 1H), 7.40 - 7.36 (t, 1H), 7.34 (a, U - 3.7 Hz, ЗН), 7.15 (а9,9 - 8.3 Gu, 1H), 4.02, 9 - 6.1 Hz, 2H), 3.58 (da, 9 - 17.4, 7.1 Hu, 1H), 2.81 (d, U - 10.3 Hu, 1H), 2.15 (5, 1H), 1.99 - 1.85 (t, 1H), 1.74 (4, U - 13.3, 6.4 Hu, 2H), 1.46 ( yes, 9 - 14.6, 9.4 Hu, ZN), 1.38 (Yii, U - 10.4 Hu, 12H), 1.25 (5, ZN). MO-IER t/ calculated 412.2032, found 413.2 (Ma-1 )k; Holding time i: 1.86 min. (Method of RH E).

Stage 6: tert-butyl (45)-4-I3-I3-Ce-chloro-6-I13-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|isulfamoyl| Ifenoxy|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

(c) and o om we i 00--- o-4MM then Ge) also - She in all Kk to in 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1 -yl|Ipyridine-3-carboxylic acid (342 mg, 0.9102 mmol) and carbonyl diimidazole (148 mg, 0.9127 mmol) were combined in tetrahydrofuran (5.5 mL) and stirred for 1 h at 50 "С Then tert-butyl (45)-2,2-dimethyl-4-13-(3-sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate (250 mg, 0.6060 mmol) was added, followed by 1,8-diazabicyclo/ 5.4.0)undec-7ene (230 μl, 1.538 mmol), and the reaction mixture was heated at 50 °C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with brine. The organic phase was separated, dried over sodium sulfate, filtered and evaporated, then purified by column chromatography on silica gel (40 g) using a gradient of 100 95 hexanes to 75595 ethyl acetate in hexane to give tert-butyl(45)-4-I3-(3 -((2-chloro-6-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine -3- carbonyl|isulfamoyl|Iphenoxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (368 mg, 79905) as an off-white solid. MO-IER t/2 calc. 769.2524, found 770.2 (MAT) k;

Holding time: 2.12 min. (Method RK 5).

Stage 7: (145)-12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia- 3,9,11-triazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 77) o o, o o, ;Z ;5 y: M y: M sy. l 9-0 M ss o 9-5 M m o gey - u se -sh

Part A: tert-butyl(45)-4-I3-(3-Ce-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl| isulfamoyl|Ifenoxy|propyl|-2,2-dimethylpyrrolidine-i-carboxylate (368 mg, 0.4778 mmol) was dissolved in dichloromethane (7.6 mL) and hydrochloric acid (4 M in dioxane) (4.0 ml of 4 M, 16.00 mmol) and stirred at room temperature for 30 min.

The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then 2 M aqueous sodium carbonate (5 mL) was added to obtain a pH of 10. The organic layer was extracted with ethyl acetate (2 x 10 mL), washed with brine, then dried over sulfate sodium, filtered and evaporated to dryness under reduced pressure.

Part B: Combine the materials from part A and potassium carbonate (345 mg, 2.496 mmol),

Cesium fluoride (115 mg, 0.7571 mmol), Z A molecular sieves and dimethyl sulfoxide (7.6 ml) in a vial, purged with nitrogen, stoppered, heated to 150 °C and stirred for 20 h.

Cooled to room temperature. The mixture was filtered, then purified by preparative

Reversed-phase HPLC using a C18 column and method 30-99 A1-B1 (acetonitrile-water n 5MM hydrochloric acid), obtaining (145)-12,12-dimethyl-8-(3-(2-(1- trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11-triazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5 (10),6,8,19,21-hexane-2,2,4-trione (compound 77) (62.1 mg, 2095) as an off-white solid. 1H NMR (400 MGu, dimethylsulfoxide-ab ) b 12.40 (5, 1H), 8.21 (a, U - 2.68 Hz, 1H), 7.85 (a, U - 8.3 Hz, 1H), 7.57 (I, U - 6.5 Hz, 2H), 7.50 (5, 1H ), 7.46 - 7.32 (t, 1H), 6.94 (a, U - 8.2 Hz, 1H), 6.12 (y, U - 2.7 Hz, 1H), 4.34 (a, U - 14.1, 5.6 Gu, ЗН), 4.21 - 4.04 (t, 1H), 2.90 - 2.78 (t, 1H), 2.71 (ai, U - 19.5, 9.2 Gu, 1H), 2.26 - 2.12 (t, 1H), 2.08 (1, 9 - 7.1 Hz, 2H ), 1.85 (da, U - 11.6, 5.5 Hz, 1H), 1.75 - 1.64 (t, 2H), 1.55 (v, 6H), 1.50 (a, U - 12.4 Hz, 1H), 1.47 - 1.36 (t, 1H), 1.28 - 1.19 (t, 1H), 0.98 - 0.93 (t, 2H), 0.88 (I, 9 - 5.2 Hz, 2H). MO-IER t/72 calc. 633.22327, found 634.2 (Ma-1)zh4; Retention time: 2.3 min (method РХ E).

Example 20: Preparation of (145)-8-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1 (23), 5,7,9,19,21-hexane-2,2,4-trione (compound 79)

oh oh

U la z s be, U shk 5 Y od ee I Mno oVyur2 sim Soi M.I vyurz vm soi b --ЙН "ad - - yo

eighth

eighth oh oh

In ovo o so ; Go Wed / o at 9, - sh | МХЙ Fe -8 Ж sim soi no ee om V, Ul vier5 o, s a;

Mn "NS yo

Stage 1: 3-(3,3-dimethylbutyl)pyrrolidin-2-one c) c) p: I Se shk Ul

To a solution of 2-pyrrolidone (32.0 g, 0.376 mol) in anhydrous tetrahydrofuran (900 mL) was added n-butyllithium (2.3 M in hexane, 343 mL, 0.790 mol) at -78 "C. The reaction mixture was stirred at same temperature for 1 h. A solution of 1-chloro-3,3-dimethylbutane (45.3 g, 0.376 mol) in anhydrous tetrahydrofuran (100 ml) was added dropwise to the reaction mixture at - 78Сb. The reaction mixture was stirred for 10 minutes at - 78 "C, and then slowly raised to room temperature. The reaction was quenched with 20 95 aqueous solution of ammonium chloride (500 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 250 ml). The combined organic layers were washed with saline (300 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with hexane (50 mL) to give 3-(3,3-dimethylbutyl)pyrrolidin-2-one (9.091 g, 1495) as a white crystalline solid. TN-NMR (250 MHz, SOSIZ) 6 5.70 (v, ri, 1H), 3.32 (t, 2H), 2.29 (t, 2H), 1.86 (t, 1H), 1.79 (t, 1H), 1.26 (t , ЗН), 0.90 (in, 9Н). E5I-M5 t/: saIs.169.1, found 169.9 (M.N) k.

Stage 2: tert-butyl (45)-4-I3-(6-K(2,6-dichloropyridine-3-carbonyl)sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o o, o ody y: ОН nН m? сх y: M y: smi --- And no si M sei M o M ke y

MN MN ney ney

2,6-dichloropyridine-3-carboxylic acid (1.14 g, 5.937 mmol) and anhydrous tetrahydrofuran (20 ml) were charged into a 250 ml round-bottomed flask under a nitrogen atmosphere. Carbonyldiimidazole (964 mg, 5.945 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 h. In a separate 100 ml flask, a solution of tert-butyl (45)-2,2-dimethyl-4-|3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (1.529 g, 3.706 mmol) in anhydrous tetrahydrofuran (10 ml) was obtained under a nitrogen atmosphere and then added through a syringe to a solution of the activated ester. 1,8-diazabicyclo|5.4.Fundec-7-ene (1.2 mL, 8.024 mmol) was added via syringe and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (50 mL) and water (30 mL). Hydrochloric acid (4 ml of 6 M,

of 24.00 mmol) and the two phases were separated. The aqueous phase was washed with saline (30 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel (80 g column) using a gradient of ethyl acetate (0 to 100 95 over 30 minutes) in hexane. Evaporation of the solvents gives tert-butyl (45)-4-I3-(6-K2,6-dichloropyridine-3-carbonyl)usulfamoyl|-2-pyridyl|amino|propyl/|-2,2-dimethyl-pyrrolidine-1- carboxylate (1.934 g, 89 95) as a white foamy solid. 1N

NMR (400 MHz, DMOO-ab) b 12.90 (rgoaa 5, 1H), 8.06 (41, 9 - 8.0, 3.1 Hz, 1H), 7.69 (a, 9 - 8.0 Hz, 1H), 7.61 (aa, U - 8.5, 7.2 Hz, 1H), 7.22 (bgoaay 5, 1H), 7.16 (y, 9 - 7.2 Hz, 1H), 6.74 (a, U - 8.5 Hz, 1H), 3.61 - 3.41 (t, 1H), 3.31 - 3.13 (t, 2Н), 2.76 (19, U - 10.5, 4.68 Gu, 1Н), 2.11 - 1.99 (t, 1Н), 1.83 (4, 9 - 14.1, 13.5, 5.9 Hz, 1ТН), 1.60 - 1.44 (t, 2H), 1.44 - 1.26 (t, 15H), 1.21 (5, ZN). MO-IER t/2 calc. 585.15796, found 586.1 (M.--1)w; Holding time: 2.02 min. (Method of RH B). The product was used in the next stage without additional purification.

Stage 3: 2,6-dichloro-M-I((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (dihydrochloride salt) o o, re; o o, re; sim s A sbsmbzea 0

MN MN is not - NSI because

In a 100 ml round-bottomed flask, tert-butyl (45)-4-IZ-((6-(2,b-dichloropyridine-3-carbonyl)usulfamoyl|-2-pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1 -carboxylate (1.923 g, 3.279 mmol) was stirred at room temperature in dichloromethane (10 mL) and hydrochloric acid (3 mL of 4 M in dioxane solution, 12.00 mmol), a white sticky precipitate formed rapidly.

Dichloromethane (10 ml) was added and the mixture was stirred at room temperature for another 2.5 hours. Another 2 ml of hydrochloric acid was added and the mixture was stirred for another 2 hours. Volatiles were removed by evaporation and the residue was evaporated in the presence of tetrahydrofuran/ethyl acetate/dichloromethane/methanol/hexane to obtain a foamy solid. Drying in high vacuum over the weekend gave 2,6b-dichloro-M-I((6-I3-((35)-5,5- dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3- carboxamide (dihydrochloride salt) (1.933 g, 105 95) as an off-white foamy solid (purity ca. 90 95 according to LCMS). 1H NMR (400 MHz, DMOO-ab) b 9.13 (rgoaa 5, 1H), 8.98 (Bgoaa 5, 1H), 8.06 (y, y - 8.0 Hz, 1H), 7.72 (a, U - 8.0 Hz, 1H), 7.62 (da, 9 - 8.5, 7.2 Hz, 1H), 7.17 (a, 9 - 7.1 Hz, 1H), 6.77 (da, U - 8.5, 0.8 Hz, 1H), 3.34 (ad, y - 11.2, 5.6 Hz, 1H), 3.24 (d,9 - 6.0 Hz, 2H), 2.80 ( 19, 9 - 11.8, 11.1, 6.0 Hz, 1H), 2.42 - 2.29 (t, 1H), 2.14 (NK, U - 7.8, 6.9 Hz, 1H), 1.93 (ai, U - 12.6, 7.8 Hz, 1H) ( Method РХ B).

From Stage 4: (145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)|hetracose-1(23 ),5,7,9,19,21-hexane-2,2,4-trione (compound o) t 90 1 o

DALO - KS sim so A sim cm A

MN MN

NS and

2,6-dichloro-M-|((6-(3-

I(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|isulfonyl|pyridine-3-carboxamide (dihydrochloride salt) (859 mg, 1.536 mmol), anhydrous MMR (13.5 mL), potassium carbonate (1.4 g, 10.13 mmol) (325 mesh), Z A molecular sieves, and cesium fluoride (285 mg, 1.876 mmol). The vessel was sealed in a nitrogen atmosphere, and the mixture was intensively stirred in an oil bath at 150°C for 22 hours. The mixture was poured into chilled water (85 mL) and acidified by adding hydrochloric acid (2.1 mL, 6 M, 12.60 mmol) (mild foaming). The resulting suspension was filtered through a ceramic funnel using a paper filter, and the solid was briefly air-dried. The solid was dissolved in dichloromethane and dried over sodium sulfate. After concentration, the solution was diluted with dichloromethane and purified by chromatography on silica gel using a gradient of ethyl acetate (from 0 to 100 95 over

30 min) in hexane. The product was eluted with 55-65 906 ethyl acetate in hexane. Evaporation of the solvents and further concentration gave (145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y 1 7.3.1.111,14.05,10)hetracose-1( 23),5,7,9,19,21-hexane-2,2,4-trione (320 mg, 54 96). IN NMR (400 MHz, Spiogoitogtt-a) b 9.19 (5, 1H), 7.80 (a, y - 7.9 Hz, 1H), 7.56 (I, Y - 7.6 Hz, 1H), 7.44 (a, 9 - 7.2 Hz . , 1H), 3.17 (y, U - 13.6 Hu, 1H), 2.96 (y, U - 10.1 Hu, 1H), 2.39 (a, 9 - 9.7

Hz, TN), 1.96 (ad, U - 12.1, 6.8 Hz, 1Н), 1.63 (а, У - 8.1 Hz, ЗН), 1.57 (y, У - 15.4 Hz, 7Н), 1.47 (а, - 9.5 Hz , 1H). MO-IER t/72 calc. 449.12885, found 450.4 (M'-1)f; Holding time: 1.76 min. (Method of RH E).

Stage 5: (145)-8-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 79)

Ge) dsh- x -5 / Their

A Fa;

Fa: y, Z H y;

MNozh SM M Me M mn to»

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (25 mg, 0.05556 mmol), 3-(3,3-dimethylbutyl)pyrrolidin-2-one (12 mg, 0.07090 mmol), Rag(aba)Z (8 mg, 0.008736 mmol), xanthophos (5 mg, 0.008641 mmol), cesium carbonate (99 mg, 0.3038 mmol) and anhydrous dioxane (400 µl). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120"C for 21 hours. The reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and subjected to reversed-phase preparative HPLC (C18) using a gradient of acetonitrile in water (from 1 to 99 95 in 15 minutes) and hydrochloric acid as a modifier. The pure fractions were collected and the solvents were evaporated to give 4.3 mg of an off-white solid. The product was further purified by flash chromatography on silica gel (4 g column) using a methanol gradient ( from 0 to 5 95 in 30 min) in dichloromethane. The pure fractions were collected and the solvents evaporated to give (145)-8-N3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl -2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2, 4-trione (compound 79) (2 mg, 6 95 ) as an off-white solid (mixture of diastereomers).IN NMR (400

MHz, DMSO-ab) 5 12.41 (5, 1H), 7.68 (y, U - 8.4 Hz, 1H), 7.63 - 7.44 (t, 2H), 7.04 (y, 9 - 7.1 Hz, 1H),

Zo 6.97 (rgoai 5, 1H), 6.70 (a, U - 8.5 Hz, 1H), 4.16 - 3.64 (t, ЗН), 3.10 (Bg 5, 1H), 2.94 (y, U - 13.3 Gu, 1H), 2.74 - 2.54 (t, 2H), 2.29 - 2.17 (t, 1H), 2.10 (re 5, 1H), 1.87 - 1.43 (t, 11H), 1.37 - 1.12 (t, 6H), 0.88 (a, 9 - 3.6 Hz, 9N). MO-IER t/: calc. 582.2988, found 583.4 (M.-1)x; Holding time: 2.25 min. (Method of RH B).

Example 21: Preparation of 12,12-dimethyl-8-(4-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11, 19,24-pentaazatetracyclo|18.3.1.111,14.05,10I pentacose-1(23),5,7,9,20 (24) 21-hexane-2,2,4-trione (enantiomer 1) (Compound 82) and 12,12-dimethyl-8-(4-(2-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo |18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 83)

se M - Bier1 7 "MVos Zivr2 o-V - -8z in Z on 0)

Se ve, Mo ZUK pev Shovak- z ZO Du fut all all about her Ho M ke; d-- va o, o oo m se M. vivrb tv, me a go Vir 7 lin M ko i NM d- nm svi hody va hody

ES o Vos-M Vos--M 7 dur ooo

My

MM M si 12 Zerv M. ss 12 faith

ES o tons Z

NM EzS bor bor ee Y pe

I am

What is epapiyoteg 1 is about epapiyoteg 2

Stage 1: tert-butyl 4-hydroxypyrazole-1-carboxylate

M. /l/ "MVos M - in 7"MVos s--e o-8,

Sodium hydroxide (16.32 g, 408.0 mmol) was added to a cold solution (0 "С) tert-butyl-4-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole-1-carboxylate (60 g, 204.0 mmol) in tetrahydrofuran (450 mL) followed by the slow addition of hydrogen peroxide (46.26 g, 41.68 mL 30 95 w/v, 408.0 mmol ). The reaction mixture was stirred at 0 "C for 10 minutes, then at room temperature for 45 minutes. The reaction mixture was cooled to 0 "C and diluted with dichloromethane (800 ml). 3M hydrochloric acid was added to pH - 2, and the organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in a small amount of dichloromethane, and the solid filtered under vacuum, washed well with additional dichloromethane and dried under reduced pressure to give tert-butyl-4-hydroxypyrazole-1-carboxylate (19.904 g, 53 95) as a white solid. TN NMR (300 MHz, DMSO-a6) 5 1.52 (5, 9H), 7.45 (a, 9-0.9 Hz, 1H), 7.51 (a, 35-0.9 Hz, 1H), 9.28 (5, 1H). MO-IER t/2 calc. 184.0848 , found 129.1 (M-С4НВА1) w Retention time: 1.73 min (Method РХН).

Stage 2: tert-butyl 4-(2-1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1-carboxylate ee U 2: MVos

2-P-(trifluoromethyl)cyclopropyl ethanol (28.2 g, 183.0 mmol) was added to a solution of tert-butyl-4-hydroxypyrazole-1-carboxylate (23.7 g, 128.7 mmol) and triphenylphosphine (50.6 g, 192.9 mmol) in tetrahydrofuran (250 ml) at 0 "C. Diisopropylazodicarboxylate (39.03 g, 38.00 ml, 193.0 mmol) was added slowly at 0 "C and the reaction mixture was stirred at 0 "C for 10 min. Then the reaction mixture was heated at 70 "C overnight. The reaction mixture was cooled to room temperature and the reaction mixture was diluted with dichloromethane (300 mL) and quenched by adding 5905 aqueous citric acid (150 mL). The organic layer was washed with saline, dried over sodium sulfate, filtered and concentrated under reduced pressure

(155 g of yellow oil). The residue was triturated with heptane and a small amount of ethyl acetate (less than 1095). The solid was filtered and washed with heptane. The filtrate was concentrated under reduced pressure (55 g of yellow oil). The residue was purified by silica gel chromatography using a gradient of 0 95 to 20 95 ethyl acetate in heptane to give tert-butyl-4-(2-P-trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1-carboxylate (27.31 g, 66 95) in the form of a white solid. IN NMR (300 MHz, DMOO-ab) 5 0.80-0.97 (t, 4H), 1.54 (5, 9H), 2.00 (I, 9-6.9 Hz, 2H), 3.99 (i 9-6.8 Hz, 2H), 7.61-7.70 (t, 1H), 7.90 (5, 1H). 196 NMR (282 MHz, dimethylsulfoxide-46b): b -68.6 (s, ZE). MO-IER t/2 calc. 320.1348, found 265.1 (M-

C4HnBA1T)x; Holding time: 2.18 min. (Method RH I).

Stage 3: 4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (hydrochloric acid salt)

L-Mvos Zh-Mn

EzS about all about ns

Hydrogen chloride (80 mL 4 M, 320.0 mmol) was added to a solution of tert-butyl-4-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-i-carboxylate) (10.63 g, 33.19 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred at room temperature overnight.

The reaction mixture was concentrated under reduced pressure to obtain /- 4-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (hydrochloric acid salt)) (8.71 g, 100 95) as an off-white solid substances. IN NMR (300 MHz, DMSO-ab) 5 0.77-0.96 (t, 4H), 1.98 (i, 3-6.9 Hz, 2H), 3.91 (1, 9U-6.9 Hz, 2H), 7.41 (5, 2H). MO-IER tp/2 calcd. 220.0823, found 221.2 (Ma1)x; Retention time: 2.43 min. (Method RH H).

Stage 4: tert-butyl //2-chloro-6-I4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylate (c) p

M. o Z and o 7 N hib To uva db tu bu» va boneo 9 o svi

EzC o 4-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (hydrochloric acid salt) (10 g, 38.963 mmol) was added to N,M-dimethylformamide (80 mL). The reaction mixture was cooled to 0"C and sodium hydride (1.87 g, 60 95 wt/wt, 46.754 mmol) was added in portions and allowed to stir for 10 min. A solution of tert-butyl 2,6-dichloropyridine-3- carboxylate (9.67 g, 38.975 mmol) in M,M-dimethylformamide (20 mL), and the reaction mixture was heated at 75 °C and allowed to stir overnight. After cooling to room temperature

At room temperature, the reaction was quenched with brine (100 ml) and extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 095 to 10 95 ethyl acetate in heptane to give tert-butyl 2-chloro-6-(4-(2-1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine) -3-carboxylate (7.68 g, 46 95) as a white solid. TN NMR (300 MHz, SOSIS) 5 0.73 (5, 2H), 0.98-1.10 (t, 2H), 1.62 (5, 9H) . a, 35-8.5 Hz, 1H). 19E NMR (282 MHz, SOSIZ) 6 -69.9 (broad s, ZE) "MO-IER t/ calc. 431.1224, found 432.1 (М--1 )w-k; Retention time: 2.56 min (Method RH I).

Stage 5: 2-chloro-6-14-2-P-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid

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EzS oh already

Trifluoroacetic acid (46.620 g, 31.5 mL, 408.86 mmol) was added to a solution of tert-butyl-2-chloro-6-I4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)pyrazol-1-yl|pyridine -C3-carboxylate (17.59 g, 40.733 mmol) in dichloromethane (150 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (175 ml) and the organic layer was washed with brine (2 X 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 2-chloro-6-I(4-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (14.82 g, 77 95) as a white solid. TN NMR (300 MHz, DMSO-ab) 6 0.81-0.97 (t, 4H), 2.04 (i, 90-6.9

Hz, 2H), 4.04-4.13 (t, 2H), 7.77 (5, 1H), 7.86 (a, 9U-8.5 Hz, 1H), 8.25 (5, 1H), 8.37 (a, U - 8.5 Hz, 1H ).

MO-ER t/» calc. 375.0598, found 376.1 (M'-1); Holding time: 3.14 min. (The method of RH N).

Stage 6: tert-butyl 4-(4-C6-C2-chloro-6-(4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2 -pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate ore;

NM. li a ke svi NM

Teny from U EzS about Teny

Vos--M ES about Vos-M

2-Chloro-6-I4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (97 mg, 0.2582 mmol), carbonyl diimidazole (45 mg, 0.2775 mmol) and tetrahydrofuran (3.0 ml). The reaction mixture was heated at 40 "C for 90 min. A solution of tert-butyl-2,2-dimethyl-4-(4-((b- sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (95 mg, 0.2227 mmol) in tetrahydrofuran (2 mL), followed by 2,3,4,6,7,8,9,10-octahydropyrimido |1,2-Aiazepine (120 μl, 0.8024 mmol). The reaction was stirred overnight at room temperature. The reaction was quenched with 1 N citric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by HPLC (20-99 965 acetonitrile:water with 0.1 95 hydrochloric acid modifier) to give tert-butyl 4-|4-

I(6-Ce-chloro-6-(4-(2-(1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|isulfamoyl|-2-pyridyliamino|butylI|-2, 2-Dimethylpyrrolidine-i-carboxylate (82.7 mg, 49 95) as a white solid NMR (400 MHz, DMSO-ab) 5 12.81 (5, 1H), 8.24 (5, 1H), 8.11 (a , 9 - 8.4 Hz, 1H), 7.87 (a, U - 8.4 Hz, 1H), 7.77 (a, 9 - 0.9 Hz, 1H), 7.61 (aa, y - 8.5, 7.2 Hz, 1H), 7.20 (y . , 1H), 3.22 (d, U - 6.5 Hz, 2H), 2.74 - 2.63 (t, 1H), 2.05 (I, U - 6.9 Hz, 2H), 1.96 (5, 1H), 1.73 (Id, U - 11.5, 6.0 Hz, 1H), 1.49 (p, U - 7.7, 7.3 Hz, 2H), 1.37 (a, U - 12.8 Hz, 9H), 1.30 - 1.12 (t, 11), 0.98 - 0.84 (t, 4H ). MO-IER tp/:2 calc. 783.27924, found 784.3 (M--1)x; Retention time: 2.28 min. (Method RH B).

Zo Stage 7: 2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-3-yl)butylamine|-2-pyridyl|Isulfonyl/|-6-(4-(2-

P-«(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide 9 chu (c) od) сОСе se єє, m s Am M SI M. a

1st and 1st St. Nm zo ES o no zone

In a round-bottom flask containing tert-butyl-4-(4-((6-(2g-chloro-6-(4-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin- 3-carbonyl|sulfamoyl|-2-pyridylyamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (118 mg, 0.1505 mmol), dichloromethane (5 mL) and trifluoroacetic acid (650 μL, 8.437 mmol) were added. The reaction was left under stirring at room temperature for 1 h. The reaction was evaporated to dryness.

A solution of saturated sodium bicarbonate was added, followed by ethyl acetate. The reaction mixture was extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered and evaporated, obtaining 2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-3-yl)butylamine|-2-pyridyl|sulfonyl| -6-(4-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide) (102 mg, 9995), which was used without further purification. MO-IER t/2 calcd. 683.2268, found 684.4 (MA) k Retention time: 1.51 min (Method RH B).

Stage 8: 12,12-dimethyl-8-(4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,24 -pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 70) (c) se u o o o

M and 5

BUT Z shchy 7 M MO M 2 M. 2 --353 DT M M

In "I am

NM EzS

Potassium carbonate (92 mg, 0.6657 mmol), cesium fluoride (45 mg, 0.2962 mmol), five molecular sieves Z A and a solution of 2-chloro-M-((6-I4 -(5,5-dimethylpyrrolidin-3-yl)/butylamine|-2-pyridyl|sulfonyl)-6-(4-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3 -carboxamide (90 mg, 0.1315 mmol) in dimethyl sulfoxide (0.8 mL). The reaction mixture was sealed and placed in an oil bath preheated to 150 C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC ( 10 95-99 956 acetonitrile:water with a modifier of 0.195 hydrochloric acid), obtaining /12,12-dimethyl-8-(4-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl )-2A6b-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2 ,4-trione (compound 70) (20.8 mg, 24 95) as a white solid. MSO-IER t/: calcd. 647.2502, found 648.4 (M.-1) k; retention time: 2.1 min (Method RH B).

Stage 9: 12,12-dimethyl-8-(4-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,24 -pentaazatetracyclo|18.3.1.111,14.05,10| pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 82) and 12,12-dimethyl-8-(4-( 2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo!18.3.1.111,14.05,10I pentacose-1( 23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 83) 2 9.6 ooo ooo hvy sm ut o he MV ih» m. MZHK nN Z w | "ShK | "MV - y - b 84 i min wa and already epapboteg 1 epapioteg 2

Racemic 12,12-dimethyl-8-(4-12-(1-«-«trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,19,24 -pentaazatetracyclo|18.3.1.111,14.05,10) pentacose-1(23),5,7,9,20(24),21- hexane-2,2,4--rione (17 mg, 0.02625 mmol) was subjected to chiral NKR chromatography using SpigaIRak A5-N (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 20-25 96 methanol (modifier MNH))/carbon dioxide at 50 ml/min with obtaining as the first of the eluted enantiomer, 12,12-dimethyl-8-(4-(2-(1-

Zo (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,24-pentaazatetracycloi 18.3.1.111,14.05,10|Ipentacose-1(23),5 ,7,9,29(24),21-hexane-2,2,4-trione (enantiomer 1) (compound 82) (7.7 mg, 90 95); MSO-IER t/2 distr. 647.2502, found 648.2 (M--1)f; Retention time: 3.18 min (method РХ 00) and 12,12-dimethyl-8-(4-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl )-2A6b-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2, 2,4-trione (enantiomer 2) (compound 83) (7.6 mg, 89 90); IN NMR (400 MHz, DMSO-46) b 12.49 (5, 1H), 7.96 (a,

U -1.0 Hu, 1H), 7.62 (a, U - 8.2 Hu, 1H), 7.62 (a, U - 26.0 Hu, 2H), 7.14 (5, 1H), 6.98 (5, 1H), 6.69 (a,

U - 44.0 Hz, 2H), 4.06 (I, 9 - 7.1 Hz, 2H), 2.86 (5, 1H), 2.04 (1, 9 - 7.0 Hz, ЗН), 1.88 - 1.78 (t, 1H), 1.65 - 1.47 (t, 7H), 1.21 (a, U - 14.6 Gu, ZN), 1.01 - 0.82 (t, 4H), MO-IER t/2 calc. 647.2502, found 648.2 (M--1) flat; Holding time: 3.18 min. (Method РХ 0).

Example 22: Preparation of (18K)-20,20-dimethyl-4-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3 ,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7 |docosa- 2,4,6,11(22),12-pentane-8,10,10-trione (Compound 84) and (185)- 20,20-dimethyl-4-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 22- pentaazatetracyclo|16.2 .1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 85)

about (is)

Ge) ra o n mya vir Nam GU uva ver2 u-m on" U o My o- o o pnia o "M Kk d- iy U ke uch iv E

ZYSK vierz -IistM Zier4 shevakazh sia m. YAKU vne, ek u

Kt - in Hm t

E go) E o o o o o

E E

E E

Stage 1: tert-butyl 2,2-dimethyl-4-I3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidin-1-carboxylate o, B 78 nom" (c) NoMm - - - w 2 Ph

My I and M KV and | in io) in-m id

Part A: To a 250 mL round-bottom flask of tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (10 g, 38.85 mmol) in dry dichloromethane (100 mL) was added triethylamine ( 8.3 ml, 59.55 mmol). The reaction mixture was cooled to 0 °C over 10 minutes and methanesulfonyl chloride (3.7 mL, 47.80 mmol) was added dropwise (exothermic, white suspension formed), and the reaction mixture was stirred for 1 hour while warming to room temperature. The reaction was then quenched cold water (150 mL) and extracted with dichloromethane (200 mL) twice.The organic layer was dried over sodium sulfate, filtered and evaporated to give the mesylate as a yellowish oil.

Part B: The crude mesylate from Part A was dissolved in M,M-dimethylformamide (50 mL) and 1H-pyrazole-3-sulfonamide (5.8 g, 39.41 mmol) was added, followed by potassium carbonate (16.3 g, 117 .9 mmol) and the reaction mixture was stirred at 70 "C for 20 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice and extracted with ethyl acetate (3 x 100 ml), the organic layers were combined, washed with water (2 - x 100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown residue was purified by chromatography on silica gel (330 g column) using a gradient from 10095 hexanes to 10095 ethyl acetate to give tert-butyl-2,2-dimethyl-4- |3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-i-carboxylate (7.6 g, 51 95) as a white solid. MO-IER t/2 calcd. 386.19876, found 387.25 (Ma-1)g Retention time: 0.61 min (Method RH A).

Stage 2: tert-butyl 4-I3-I3-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazole- 1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o o o so re) ry 78 and НМ 7 0-4 sei M 0-4 sei tm 5/7 va U. 57 Z o

E. M. E

E -M-o E - o 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (458 mg, 1.219 mmol) and di (imidazol-1-yl)umethanone (208 mg, 1.283 mmol) was combined in tetrahydrofuran (5 mL) and stirred for 120 min at 50 "C. Then, tert-butyl-

2,2-Dimethyl-4-(3-(3-sulfamoylpyrazol-1-yl)/propyl|pyrrolidine-i-carboxylate (388 mg, 1.004 mmol) and then 1,8-diazabicyclo/5.4.F01undec-7- en (300 μL, 2.006 mmol), and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution followed by brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then it was purified by chromatography on silica gel using a gradient from 100 95 hexanes to 90 95 ethyl acetate in hexane to obtain tert-butyl-4-I(3-(3-(2-chloro-6-I3-(2-(1-"trifluoromethyl )cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (247 mg, 33 95) as a white solid substances. 1H NMR (400 MHz, Spiogoitogit-a) b 9.82 (5, 1H), 8.30 (y, Y - 2.9 Hz, 1H), 8.22 (a, Y - 8.5 Hz, 1H), 7.73 (y, 9 - 8.5 Gu, 1H), 7.47 (y, U - 2.4 Hz, 1H), 7.04 (a, 9 - 2.3 Hz, 1H), 5.96 (a, U - 2.9 Hz, 1H), 4.39 (I, 7 - 7.2 Hz, 2H), 4.19 (U - 7.1 Hz, 2H), 3.75 - 3.51 (t, 1H), 2.83 (Y, U - 10.3 Hz .

ОН), 1.33 (5, ЗН), 1.30 (а, 9У - 13.3 Hz, 2Н), 1.23 (5, ЗН), 1.05 - 1.00 (t, 2Н), 0.76 - 0.70 (t, 2Н). MO-

IER tt/2 calc. 743.248, found 744.3 (M--1) zhk; Holding time: 0.86 min. (Method of RH A).

Stage 3: 20,20-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 ... city of SO (di;

From the same nn od 5-7 ud BC sh

IS

Part A: Solution of tert-butyl 4-I3-3-C2-chloro-6-I3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|pyrazole- 1-yl|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (247 mg, 0.3319 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (260 μL, 3.398 mmol) were stirred at room temperature for 4 h Then the solvents were evaporated, the residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was removed and dried under high vacuum.

Part B: The residue from part A was dissolved in dimethylsulfoxide (b ml), molecular sieves with A were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (153 mg, 1.007 mmol) and potassium carbonate (142 mg, 1.027 mmol) were then added and the reaction mixture was heated at 130 °C overnight. The reaction mixture was filtered through a disc filter

Zo Umpaytap (Rigadies 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient run of 50-90 9o mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain 20,20-dimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2 (7),3,5,11(22),12-pentane-8,10,10-trione (80 mg, 40 95) in in the form of a white solid. MO-IER t/7 calc. 607.2189, found 608.1 (M--1) zhk; Holding time: 2.07 min. (Method of RH B).

Stage 4: (18K)-20,20-dimethyl-4-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3, 9,14, 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 84 ) and (185)-20 ... ,14.02,7 |docosa-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 85) o o o o o o o d y: M o M sia M

E d- Kk she still Kk sh

Racemic /20,20-dimethyl-4-(3-12-11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 22-pentaazatetracycloi16 .2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (80 mg) was subjected to chiral separation using NKR chromatography using Spiga! Cancer A5-H (250 X 10 mm), column, particle size 5 μm) with mobile phase 27 Us acetonitrile:methanol, 7395 carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl -- 24 mg/ml in acetonitrile:methanol (90:10)) with obtaining as the first eluted enantiomer (18K)-20,20-dimethyl-4-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy) - 1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,22-pentaaztetracyclo|16.2.1.111,14.02,7 |docosa-2,4,6,11(22),12-pentaene -8,10,10-trione (Compound 84) (27 mg, 27 90); IN NMR (400 MHz, Spiogoitogt-

a) b 8.82 (5, 1H), 8.16 (y, 9 - 2.68 Hz, 1H), 7.66 (a, 9U - 8.2 Gu, 1H), 7.46 (a, U - 2.4 Hz, 1H), 7.06 (y, 9 - 2.3 Hz, 1H), 6.96 (a, U - 8.2 Hz, 2H), 5.86 (a, U - 2.8 Hz, 1H), 4.39 (j, U - 7.1 Hz, 2H), 4.31 (4.9 - 13.3, 3.3 Hz, 1H), 3.91 (14, U - 12.6, 2.7 Hz, 2H), 2.81 - 2.66 (t, 2H), 2.19 - 2.07 (t, ЗН), 1.97 (1.9 - 10.1 Hz, 1H ), 1.75 (yes, U - 11.7, 5.3 Hz, 1H), 1.57 (5, ЗН), 1.54 (5, ЗН), 1.46 (I, У - 12.2 Hz, 1Н), 1.08 - 0.99 (t, 2Н) , 0.81 - 0.71 (t, 4H), MO-IER t/2 calc. 607.2189, found 608.1 (Ma-1); Holding time: 2.07 min. (Method of RH B) apa a5 She 5esopa epapioteg o eiYshe (185)-20,20-dimethyl-4- (3-22-11-(iogoteiitu!)susiorgoruCeiohu)-1H-ruga?o1-1-yl)-10A6 -thia-1,3,9,14,22-pentaazatetracyclo I|16.2.1.111,14.02,7|dosose-2,4,6,11(22),12-repiacepe-8,10,10-trione (Compound 85) (31.5 mg, 31 95); IN NMR (400 MHz, Spiogogtogit-a) b 8.44 (5, 1H), 8.17 (a, U - 2.7 Hz, 1H), 7.68 (a, 9-82 Hz, 1H), 7.48 (a, 9 - 2.3 Hz . ), 4.33 (y, U - 3.5 Hz, 1H), 3.93 (Y, U - 12.3 Gu, 1H), 2.74 (5, 1H), 2.22 - 2.12 (t, 2H), 2.09 (I, U - 7.2 Hz . 12.2 Gu, 1H), 1.06 - 1.00 (t, 2H), 0.89 - 0.68 (t, 4H), MO-IER t/2 calc. 607.2189, found 608.1 (M'-1)k; Holding time: 2.07 tips (Method RH B).

Example 23: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9 ,11-triazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (enantiomer 1) (compound 95) and 12, 12-dimethyl-8-(3-12-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11-triazatetracyclo|18.2. 2.111,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (enantiomer 2) (compound 96) chu v) oo 7 o o Ne van on G still has

EzS because ooo bad flax

Go! pev (o) Zier Z o Am M si o Zier4 i m y, o or IY chu ? chu o-th "MM M M o 0-07 M M (0) o-th M M M o ek code ek t Yaru epapioteg 1 epapioteg2

Stage 1: tert-butyl 2,2-dimethyl-4-(4--4-sulfamoylphenoxy)butyl|pyrrolidine-1-carboxylate in y "0 mode 4 m o

4-Hydroxybenzenesulfonamide (319 mg, 1.842 mmol) and M,M-dimethylformamide (12.88 mL) were added to a 50 mL flask. Tert-butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (643.8 mg, 1.842 mmol) and potassium carbonate (891 mg, 6.447 mmol) were added to the mixture at room temperature and stirred at 50 C during the night.

It was cooled to room temperature and poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml), the organic layers were combined, washed with water (2 x 100 ml), dried

Zo (sodium sulfate), filtered and concentrated to a brown residue, which was purified by chromatography on silica gel using a gradient from 10095 hexanes to 100 95 ethyl acetate to give tert-butyl-2,2-dimethyl-4-(4-(4-sulfamoylphenoxy) butyl|pyrrolidine-1-carboxylate (416.1 mg, 53 9b5) as a light orange oil.IN NMR (400 MHz, dmMso-ab) b 7.46 (I, 9 - 8.0 Hu, 1H), 7.39 - 7.33 (t, 2H), 7.31 (5, 2H), 7.13 (a, U - 7.8 Hz, 1H), 4.02 (i, y -6.0 Hz, 2H), 3.85 - 3.67 (t, 1H), 1.88 (da, 9 - 11.6, 6.6 Hz, 2H), 1.79 - 1.61 (t, 4H), 1.51 (ad, y - 37.7, 5.8 Hz, 2H), 1.38 (5, 12H), 1.24 (5, ZN). MO-IER t/2 calcd 426.21884, found 427.3 (MA1) k Retention time: 0.75 min (RH Method A).

Stage 2: tert-butyl 4-(4-I4-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|phenoxy) |butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

(c) oo 'oy

My wife is everything to me

MTMO I -- 7 0th by om MY oo in EZS

In a vial with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (549.7 mg, 1.463 mmol) and carbonyl diimidazole (237.2 mg, 1.463 mmol) was combined in tetrahydrofuran (5.971 mL) and stirred for 120 min at 50 "C with the lid open. Then tert-butyl-2,2-dimethyl-4-|(4- (4-sulfamoylphenoxy)butyl|pyrrolidine-1-carboxylate (416.1 mg, 0.9755 mmol) in tetrahydrofuran (7.964 mL), followed by 1,8-diazabicyclo|5.4.0)undec-7-ene (297, 0 mg, 291.7 μl, 1.951 mmol), and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate, which gave very poor resolution. Fractions containing product were combined and concentrated, then re purified by silica gel chromatography using a shallow gradient from 100 95 dichloromethane to 20 95 methanol/dichloromethane to give tert-butyl 4-(4-(4-C2-chloro-6-(3-(2-11-"trifluoromethyl)cyclopropyl) ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|isulfamoylIfenoxy|butylI|-2,2-dimethylpyrrolidine-1-carboxylate (596 mg, 7895) as a light yellow solid. MO-IER t/2 calc. 783.268, found 784.2 (Mat) k;

Holding time: 2.54 min. (Method of RH B).

Stage C: 2-chloro-M-I(4-(4-(5,5-dimethylpyrrolidin-3-yl)butoxy|phenyl|Isulfonyl-b-(3-(2-(11- (trifluoromethyl)cyclopropyl)|ethoxy Pyrazol-1-yl Ipyridine-3-carboxamide

Tert-butyl 4-I4-(4-Ce-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|phenoxy|butyl|- 2,2-Dimethylpyrrolidine-1-carboxylate (596 mg, 0.7599 mmol) was dissolved in dichloromethane (2.600 mL), and trifluoroacetic acid (3.975 g, 2.686 mL, 34.86 mmol) was added to the mixture and stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol to ensure solubility, and the layers were separated.The organic layer was concentrated by rotary evaporation followed by a high vacuum pump to give 2-chloro-M-I (4-(4-(5,5-dimethylpyrrolidine-3-

Zoyl/butoxy|phenyl|sulfonyl-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide) (403.3 mg, 78 95) in the form of dirty white solid MO-IER t/: calcd 683.2156, found 684.2 (MT) k Retention time: 0.66 min (RC Method A).

Stage 4: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11 -triazatetracyclo|18.2.2.111,14.05,190|Ipentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (Compound 89) o 9 ooo -Z p

OO. dO o - M s o o - MM o v i sia med

To a solution of /2-chloro-M-(4-I(4-(5,5-dimethylpyrrolidin-3-yl/butoxy|phenyl|sulfonyl-6-I(3-(2-(1- (trifluoromethyl))cyclopropyl |ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (403.3 mg, 0.5895 mmol) in dimethylsulfoxide (16.13 ml) was added potassium carbonate (488.7 mg, 3.536 mmol), cesium fluoride (107 .5 mg, 0.7077 mmol) and a small amount of molecular sieves Z A. The resulting mixture was stoppered and heated to 165 "C for 18 hours. Then the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried (sodium sulfate), filtered, and concentrated to a tan amorphous solid, which was purified by chromatography on silica gel using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give 12,12-dimethyl-8-(3-12- |1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9,11-triazatetracyclo|18.2.2.111,14.05,10|pentacose-1( 22),5,7,9,20,23-hexane-2,2,4-trione (spo onion 89) (80 mg, 21 90). TN NMR (400 MHz, DMSO-4b) b 12.22 (5, 1H), 8.19 (j, 9 - 2.8 Hz, 1H), 8.08 (aa, Y - 8.6, 2.5 Hz, 1H), 7.88 (a, y - 8.3 Hz, 1H), 7.77 (aa, U - 8.7, 2.5 Hz, 1H), 7.34 (ada, 9 - 16.6, 8.7, 2.5 Hz, 2H), 6.92 (a, U - 8.3 Hz, 1H), 6.11 ( a, 9 5 2.7

Hz, 1H), 4.40 (i, U - 4.8 Hz, 2H), 4.31 (i, U - 7.0 Hz, 2H), 2.40 (5, 1H), 2.07 (1, U - 7.1 Hz, 2H), 1.95 ( and,

U - 29.5 Hz, 2H), 1.76 (I, U - 6.5 Hz, 2H), 1.59 (5, 1H), 1.52 (y, U - 6.7 Hz, 6H), 1.46 (y, U - 12.3 Gu, 1H) . ). MO-IER t/2 calc. 647.23895, found 648.2 (Ma1)-; Holding time: 2.37 min. (Method of RH B).

Stage 5: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11 -triazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (enantiomer 1) (compound 95) and 12,12- dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11- triazatetracyclo|18.2.2.111 ,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (enantiomer 2) (compound 96) code epapioteg 1 epapboteg 2

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9,11- triazatetracyclo|18.2.2.111,14.05,10| pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (compound 89) (72.1 mg, 0.1101 mmol) was subjected to chiral resolution using

NKR-chromatography using SpigaISe! OB-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 35 95 acetonitrile/methanol (90:10)/65 95 carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10) with obtaining as the first eluted enantiomer /12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1 H- pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11-triazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5,7,9,20,23-hexaene- 2,2,4-trione (enantiomer 1) (compound 95) (21.9 mg, 61 95); IN NMR (400 MHz, DMSO-ab) b 12.23 (5, 1H), 8.19 (a, U - 2.8 Hu, 1H), 8.08 (da, U - 8.6, 2.4 Hz, 1H), 7.88 (j, 9 - 8.3 Hz, 1H), 7.76 (aa, U - 8.7, 2.4 Hz, 1H), 7.34 (aa, 9

Zo - 16.3, 8.7, 2.5 Hz, 2H), 6.92 (a, U - 8.3 Hz, 1H), 6.11 (y, U - 2.7 Hz, 1H), 4.40 (I, U - 4.9 Hz, 2H), 4.31 ( I, 9 - 7.0 Hz, 2H), 3.17 (a, - 5.2 Hz, 1H), 2.40 (a, 9 - 10.3 Gu, 1H), 2.07 (i, U - 7.1 Hz, 2H), 1.92 (i, - 5.4 Hz, 2H), 1.81 - 1.72 (t, 2H), 1.58 (a, 9 - 15.1 Hz, 1H), 1.53 (5, ЗН), 1.51 (5, ЗН), 1.33, 9 - 13.3 Gu, 1Н) , 1.12 - 0.98 (t, 2H), 0.98 - 0.94 (t, 2H), 0.88 (NK, U - 5.6, 2.4 Hz, 2H), 0.66 (a, y - 13.0

Hz, 1H), MO-IER t/2 calc. 647.23895, found 648.2 (M--1); Holding time: 2.34 min (method

LC B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6- thia-3,9,11-triazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (enantiomer 2) (compound 96) (18.75 mg, 52 95); MO-IER t/2 calcd. 647.23895, found 648.2 (Ma1)k; Retention time: 2.33 min (method RH B).

Example 24: Preparation of (145)-8-I3-(3,3-dimethylbutyl)-4,4-dimethyl-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6-thia-3,9,11 ,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (salts of hydrochloric acid) (Compound 98) (c) (o; o o" vier1 oto zu vier2 zo Vivr Z -- Ye - z shchi -- z ---shz" o oo Hu (o) -5 -8

My sim My - 4 same MM m My "NS

Stage 1: 1-benzyl-4,4-dimethylpyrrolidin-2-one

0); o) on the 2nd

To a 100 mL round-bottom flask charged with 4,4-dimethylpyrrolidin-2-one (524 mg, 4.631 mmol) was added tetrahydrofuran (25 mL) followed by 2-methylpropan-2-olate sodium salt (590 mg, 6.139 mmol) , and the mixture was stirred at room temperature for 30 min. Bromomethylbenzene (1000 μl, 8.408 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (-15 mL), and the crude mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude reaction mixture was purified by chromatography on silica gel (095 - 60 95 ethyl acetate in hexane) to give a gradient of 1-benzyl-4,4-dimethyl-pyrrolidin-2-one (834 mg, 89 90) as a clear oil. MSO-IER t/2 calc. 203.13101, found 2041 (Ma1)x; Holding time: 1.3 min. (Method of RH B).

Stage 2: 1-benzyl-3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one o; at);

A 100 mL round-bottom flask was charged with 1-benzyl-4,4-dimethylpyrrolidin-2-one (834 mg, 4.103 mmol) and tetrahydrofuran (20 mL), and the reaction flask was purged with nitrogen for 5 minutes.

The reaction flask was cooled to -78 "C, butyllithium (2.1 mL, 2.5 M, 5.250 mmol) in hexane was added dropwise, and the mixture was stirred at -78 "C for 1 hour. 1-Bromo-3,3-dimethylbutane (700 μL, 4.970 mmol) was added dropwise, and the reaction mixture was stirred and slowly warmed to room temperature over 18 hours. The reaction was quenched with water (10 mL) and brine (10 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were dried over magnesium sulfate and concentrated by massio. The crude reaction mixture was purified by chromatography on silica gel (0-40 95 ethyl acetate in a gradient of hexanes) to give 1-benzyl-3-(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (107 mg, 9 95) in in the form of a transparent oil.

MO-ER t/2 calc. 287.2249, found 288.1 (M--1); Holding time: 2.15 min. (Method of RH B).

Stage 3: 3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one (0) (o) ho shi z i

To a 50 mL nitrogen-purged flask charged with 1-benzyl-3-(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (107 mg, 0.3723 mmol) was added propan-1- amine (3 mL) and ethane-1,2-diamine (200 µL, 2.992 mmol). The solution was cooled to -30 "C and a strip of lithium was added

From wire (4 cm, cut into 4 smaller pieces and washed with hexane to remove excess oil).

The flask was again equipped with a septum, and the reaction mixture was stirred vigorously with slight heating to -20 "C. As a result, a blue color formed around the lithium wire, which briefly passed into the solution, and the reaction mixture was allowed to stir until the solution turned dark blue (- 20 min). Water (x 15 mL) was added, larger pieces of lithium were removed, the mixture was warmed to room temperature and stirred for 10 min. The crude mixture was extracted with ethyl acetate (3 x 20 mL), the combined organic the extracts were washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated in bulk to give crude 3-(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (115 mg, 157,965 (crude product, containing impurities)) in the form of a yellow oil, which was used without further purification. MO-IER t/7 calc. 197.17796, found 198.1 (M--1)k; Retention time: 1.58 min. (Method RK B).

Stage 4: (145)-8-I3-(3,3-dimethylbutyl)-4,4-dimethyl-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (hydrochloric acid salt) ( Compound 98)

oooh oooh

X/; M/ o u zmu xx o zy zmu xx as cm m MOM m where and zl -NSI

Crude 3-(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (45 mg, 0.2281 mmol) was introduced into a 4 ml vial, (145)-8-chloro-12,12- dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2 ,4-trione (25 mg, 0.05373 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthene-4-ylodiphenylphosphane (8 mg, 0.01383 mmol), tris(dibenzylideneacetone)dipalladium (0) (13 mg 0.01420 mmol), cesium carbonate (25 mg, 0.07673 mmol) and dioxane (1 ml). The free space above the product was purged with nitrogen, the test tube was closed and the reaction mixture was stirred at 120 "C for 18 hours. After cooling to room temperature temperature, the crude mixture was diluted with ethyl acetate (- 30 ml) and washed with 1.0 M aqueous citric acid (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated by massio. The crude residue was dissolved in a minimum amount of dimethyl sulfoxide (0.4-1 ml) and subjected to purification by HPLC (reverse phase

C18, 99:1-14:99 water:acetonitrile, modifier hydrochloric acid). Then the fractions were concentrated in vacuo and the residue was purified by chromatography on silica gel (0 95-70 Fo) gradient of ethyl acetate in hexane, obtaining (145)-8-I3-(3,3-dimethylbutyl)-4,4-dimethyl-2-oxopyrrolidine- 1-yl|I-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19 (23),20-Hexane-2,2,4-trione (hydrochloric acid salt) (compound 98) (4 mg, 11 95) as an off-white solid. 1H NMR (400 MHz, DMSO-a6) b 12.42 (5, 1H), 7.66 (aa, 9 - 8.3, 3.2 Hz, 1H), 7.52 (ada, U - 22.6, 14.6, 8.2 Hz, 2H), 7.03 ( y, 9 - 7.2 Hz, 1H), 6.92 (y, U - 32.0 Hz, 1H), 6.69 (a, U - 68.7 Hz, 1H), 4.46 - 3.82 (t, ЗН), 3.83 - 3.41 (t, ЗН ), 3.09 (in, 1H), 2.93 (y, U - 13.3

Gu, 1H), 2.80 - 2.63 (t, 1H), 2.40 - 2.23 (t, 1H), 2.17 - 1.98 (t, 1H), 1.90 - 1.68 (t, 2H), 1.68 - 1.38 (t, 8H), 1.28 (y, 9U - 40.1 Gu, 5H), 1.18 (a, y - 5.6 Hz, 2H), 1.02 - 0.70 (t, 9H). MO-IER t/27 calc. 610.33014, found 611.2 (M--1)k; Holding time: 2.38 min. (Method of RH B).

Example 25: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3,9 ,11-triazatetracyclo|17.2.2.111,14.05,10|hetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (enantiomer 1) (compound 99) and 12, 12-dimethyl-8-(3-12-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11-triazatetracyclo!|17.2 .2.111,14.05,10|tetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (enantiomer 2) (compound 100)

Fe -8 about tey "a se about OM "7 era. 7. M.M is Si bert 0-42 he no ne de 1 che 9 oo vaad lyano o pev o Verz 0-4 se o Zer4

Shchi k and Shchi Kk more

VosM NM ooo 1 che T 9 , 5. o-4 MTM TM (o) 0o-th 0-th M MO o uk code ek Uk nya Uk zo epapioteg 1 epapioteg 2

Stage 1: tert-butyl 2,2-dimethyl-4-(3--4-sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate

OM Chui V Phi

VosMm NI Phi -- (I am about him

VosmM

4-Hydroxybenzenesulfonamide (471.1 mg, 2.720 mmol) and M,M-dimethylformamide (13.69 mL) were added to a 50 mL flask. Tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (912.4 mg, 2.720 mmol) and potassium carbonate (1.316 g, 9.520 mmol) were added to the mixture at room temperature and stirred at at room temperature for 3 h, then heated to 50"C overnight. Cooled to room temperature and poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml), combined organic layers, washed with water (2 x 100 ml ), dried (sodium sulfate), filtered and concentrated to a brown residue, which was purified by chromatography on silica gel using a gradient from 100 95 hexanes to 100 95 ethyl acetate to obtain tert-butyl-2,2-dimethyl-4-IZ3--4- sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate (578.3 mg, 52 95) as a light orange oil. NMR (400 MHz, DMSO-ab) b 7.46 (I, 9 - 8.0 Hz, 1H), 7.39 - 7.33 (t, 2H), 7.31 (5, 2H), 7.13 (9, U - 7.8 Hz, 1H), 4.02 (1, 9 - 6.0 Gu, 2H), 3.85 - 3.67 (t, 1H), 1.88 ( aa, U - 11.6, 6.6 Hu, 2H), 1.79 - 1.6 1 (t, 4H), 1.51 (yes, 9 - 37.7, 5.8 Hz, 2H), 1.38 (5, 12H), 1.24 (5,

ZN). MO-IER t/2 calc. 412.2032, found 413.3 (M'a-1)j; Holding time: 0.71 min. (The method of RH

AND).

Stage 2: tert-butyl 4-I3-I4-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|phenoxy|propyl |-2,2-dimethyl-pyrrolidine-1-carboxylate gode) d. ooo

IF) nm fe zh in 0-0 M s - 0-7 My (in) everything your

VosM

VosM

In a vial with a volume of 20 ml, 2-chloro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (790.2 mg, 2.103 mmol) and carbonyl diimidazole (341.0 mg, 2.103 mmol) was combined in tetrahydrofuran (b mL) and stirred for 120 min at 50 C with the lid open. Then tert-butyl-2,2-dimethyl-4-|3-(4 - sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate (578.3 mg, 1.402 mmol) in tetrahydrofuran (10 mL), followed by 1,8-diazabicyclo(/5.4.Fundec-7-ene (426.9 mg, 419, 4 μl, 2.804 mmol), and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a shallow gradient from 100 95 hexanes to 100 95

From ethyl acetate, which gave very poor resolution. Fractions containing the product were combined and concentrated, then repurified by chromatography on silica gel using a shallow gradient from 100 956 dichloromethane to 20 95 methanol/dichloromethane to give tert-butyl 4-(3-I4-C(2-chloro- 6-(3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|isulfamoyl|Ifenoxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (953.1 mg, 88 95) in the form of a light yellow solid. MO-IER Ip/2 calculated 769.2524, found 770.1 (Ma) zhk;

Holding time: 2.49 min. (Method of RH B).

Stage C: 2-chloro-M-I(4-I3-(5,5-dimethylpyrrolidin-3-yl)upropoxy|phenyl|sulfonyl-b-I3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazole- 1-yl|Ipyridine-3-carboxamide

VosmM us

tert-butyl 4-N3-(4-C2n-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|Ifenoxy|propyl|- 2,2-Dimethylpyrrolidine-1-carboxylate (953.1 mg, 1.237 mmol) was dissolved in dichloromethane (4.158 mL) and trifluoroacetic acid (6.471 g, 4.372 mL, 56.75 mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min.

The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol to ensure solubility, and the layers were separated. The organic layer was concentrated on a rotary evaporator followed by drying in a vacuum, obtaining //2-chloro-M-I4-I3-(5,5-dimethylpyrrolidin-3-yl)upropoxy|phenyl|sulfonyl-6-I(3-(2 -(11-(trifluoromethyl)cyclopropyl|ethoxy |pyrazol-1-yl|pyridin-

Z-carboxamide (738.1 mg, 89 95) as an off-white solid. MO-IER t/7 calc. 669.19995, found 670.3 (M'-1) zhk; retention time: 0.65 min. (Method of RH A).

Stage 4: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11 -triazatetracyclo|17.2.2.111,14.05,10)hetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (Compound 88) boron boron and m? xx m? in the spring it is 0-7 -- -35- 0-7 not - and in -Y pod

NM

To a solution of 2-chloro-M-I4-IZ3-(5,5-dimethylpyrrolidin-3-yl)upropoxy|phenyl| sulfonyl-b-I(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide) (738.1 mg, 1.101 mmol) in dimethyl sulfoxide (29.52 ml) was added carbonate potassium (912.8 mg, 6.605 mmol), cesium fluoride (200.7 mg, 1.321 mmol) and a small amount of molecular sieves Z A. The resulting mixture was closed and heated to 130 "C for 16 hours. Heating was continued at 150 "C for 16 hours.

It was heated to 170 C and stirred for 3 h, then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried (sodium sulfate), filtered, and concentrated to a tan amorphous solid, which was purified by chromatography on silica gel using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give 12,12-dimethyl-8-(3-2 -11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11-triazatetracyclo!|17.2.2.111,14.05,10|hetracose-1( 21),5,7,9,19,22-hexane-2,2,4-trione (30 mg, 4 95) as a white solid. 1H NMR (400 MHz, DMSO-ab) b 12.13 (5, 1H), 8.17 (a, 9 -

Zo 2.8 Hz, 1H), 8.06 (a, 9 - 7.8 Hz, 1), 7.83 (a, U - 8.3 Gu, 1Hn), 7.78 (a, 9 - 8.6 Hz, 1H), 7.30 (aa, y - 8.68 , 2.4 Hz, 1H), 7.19 (yes, 9 - 8.6, 2.4 Hz, 1H), 6.89 (a, U - 8.3 Hz, 1H), 6.10 (a, U - 2.7 Hz, 1H), 4.52 (a, U - 12.1 Hu, 1H), 4.30 (Her, U - 7.0 Hz, 2H), 4.27 - 4.17 (t, 1H), 2.07 (, U - 7.1 Hz, 2H), 1.96 (5, 2H), 1.75 (5, 1H), 1.69 (y, U - 12.2 Hz, 1H), 1.53 (5, 5H), 1.46 (5, ЗН), 1.44 - 1.36 (t, 2H), 1.05 (5, 1H), 0.98 - 0.93 (t , 2H), 0.90 - 0.84 (t, 2H). MO-IER t/: calc. 633.22327, found 634.1 (M.-1) k;

Holding time: 2.28 min. (Method of RH B).

Stage 5: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11 -triazatetracyclo|17.2.2.111,14.05,10)hetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (enantiomer 1) (compound 99) and 12,12- dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3,9,11-triazatetracyclo!|17.2. 2.111,14.05,10|tetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (enantiomer 2) (compound 100) 1 chu 1 9 0-45 MTM ОМ ге) 0th 0-7 M МОМ о ек коде вк де ек екод епапиотек 1 епапиотег 2

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3,9,11- triazatetracyclo!|17.2.2.111,14.05,10)hetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione (27.2 mg, 0.04292 mmol) was subjected to chiral separation by means of NKR chromatography using SpigaI (Se! O0-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 4295 acetonitrile/methanol (90:10)/58 9o carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl of a 24 mg/ml solution in acetonitrile/methanol (90:10) with obtaining as the first eluted enantiomer /12,12-dimethyl-8-(3-12-11- ( trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11-triazatetracyclo!|17.2.2.111,14.05,10|tetracose-1(21),5 ,7,9,19,22-hexane-2,2,4-trione (enantiomer 1) (compound 99) (10.22 mg, 75 95) as a white solid; 1H NMR (400 MHz, DMSO- ab) b 12.13 (5, 1H), 8.17 (a, U - 2.8 Hz, 1H), 8.07 (a, U - 8.4 Hz, 1H), 7.83 (a, U - 8.3 Hz, 1H), 7.79 (0, 9 - 8 .8 Hz, 1H), 7.31 (ad, y - 8.6, 2.5 Hz, 1H), 7.20 (ad, U - 8.6, 2.4 Hz, 1H), 6.90 (a, U - 8.3 Hz, 1H), 6.10 (a , 9 - 2.68 Hz, 1H), 4.52 (9, U - 11.9 Gu, 1H), 4.30 (1, 9 - 7.1 Hz, 2H), 4.26 - 4.16 (t, 1H), 2.07 (U - 1.1 Hz, 2H ), 1.96 (5, 2H), 1.77 - 1.64 (t, 2H), 1.55 (5, 1H), 1.53 (5, ЗН), 1.48 (5, 1Н), 1.46 (v, ЗН), 1.38 (аа, U 2 22.7, 11.1 Hu, 2H), 1.04 (a, y - 8.2 Hu, 1H), 0.99 - 0.92 (t, 2H), 0.89 (y, U - 11.6 Hu, 2H), MO-IER t/ cal. 633.22327, found 634.1 (M'-1) k; Holding time: 2.25 min (method RH

B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3 ,9,11-triazatetracyclo|17.2.2.111,14.05,10|tetracose-1(21),5,7,9,19,22-hexane-2,2,4-trione. (enantiomer 2) (compound 100) (9.72 mg, 71 95) as a white solid; MO-IER Ip/2 div. 633.22327, found 634.1 (M--1) zhk; Holding time: 2.25 min (method RH B).

Example 26: Preparation of (145)-8-I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (Compound 102) (e)

SI with Zier 1

Ko i Mo A ---e- o ee; o se v-y xx y U Dh veer2 ky Kv;

Stage 1: 3-(4,4-dimethylpentyl)pyrrolidin-2-one) c)

SI MN

Who am I, MN?

A 2.5 M solution of n-butyllithium in hexane (43.6 ml, 0.109 mole), and

The reaction solution was stirred at this temperature for 1 hour. A solution of 1-chloro-4,4-dimethylpentane (7.34 g, 54.52 mmol) in anhydrous tetrahydrofuran (20 mL) was added slowly. After the addition was complete, the solution was stirred at -78°C for 20 minutes before it was gradually warmed to ambient temperature. 20 95 aqueous ammonium chloride solution (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 150 mL) , and the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. (3.86 g, 3995) as a white solid. LA NMR (250 MHz, SOSIS) b (rrit): 7.51 (5, 1H), 3.12 (t, 2H), 2.15 (t, 2H), 1.60 (t , 2H), 1.29-1.11 (t, 5H), 0.86 (5, 9H). MO-IER tp/2 calculated 183.16, found 184.2 (M'-1)k. Retention time: 4.66 min. (Method

РХ 0).

Stage 2: (145)-8-I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 102)

boo o , 9) oo o to bu y, s M Nm t M

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (25 mg, 0.05373 mmol), 3-(4,4-dimethylpentyl)pyrrolidin-2-one (29 mg, 0.1582 mmol) (crude material, purity unknown), Rag(ara)z (10 mg, 0.01092 mmol), xanthophos (6 mg, 0.01037 mmol), cesium carbonate (87.52 mg, 0 .2686 mmol) and anhydrous dioxane (0.4 ml). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120 "C for 21 hours. The reaction mixture was diluted with dimethyl sulfoxide (700 μl), microfiltered and subjected to reversed-phase preparative HPLC (C18) using a gradient of acetonitrile in water (from 1 to 99 95 in 15 min) and hydrochloric acid as a modifier. Pure fractions were collected, a little brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporation of the solvents gave 8 mg of solid. The product was purified by flash by chromatography on silica gel (4 g column) using a gradient of methanol (from 0 to 5 95 in 30 min) in dichloromethane. The pure fractions were collected and the solvents were evaporated to obtain (145)-8-I3-(4,4-dimethylpentyl)-2 -oxopyrrolidin-1-yl|- 12,12-dimethyl-2А6-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7, 9,19(23),20-hexane-2,2,4-trione (Compound 102) (5.5 mg, 17 95) in the form of TV a white mixture of diastereomers. IN NMR (400 MHz, DMSO-ab) b 12.42 (5, 1H), 7.68 (a, U - 8.5 Hz, 1H), 7.61 - 7.48 (t, 2H), 7.04 (a, 9 - 7.1 Hz, 1H) . , 1H), 2.74 - 2.60 (t, 2H), 2.33 - 2.18 (t, 1H), 2.10 (Big 5, 1H), 1.86 - 1.66 (t, 4H), 1.65 - 1.44 (t, 9H), 1.37 - 1.15 (t, 6H), 0.87 (a, U - 1.8

Hz, 9H). MO-IER t/2 calc. 596.31445, found 597.4 (M.-1)xzh; Holding time: 2.29 min. (Way

RK B).

Example 27: Synthesis of 8-13-(I(dispiro(2.0.2.1)|heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11, 18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 106 ) and 8-I3- (dispiro(2.0.2.1|heptan-7-ylomethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo 17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (enantiomer 2) (Compound 107) (in ) zivr1 shk Bior2 vir z mo vier4 a p na nn NN U early (in) (o)

Ba Zer 5 Va Zeer b V -k beaver7 Z -n ' rea Vivr8

SI M SI

(o) (c) ra z 9 mA r 9 vyura mm On 5 vier 10 0-47 OO - Y" -.zh o-4 MTM toi 7 vosm Ma 0-22 f- fr o or o o o

M. 2 My Zivr 11 M. 2 M. 2 Zer12 0-2 M M a zh o-i M MO s -- D-zhk f- ta oi V ta BoVyy still ek ozh. stro and om. soon re Or zo epapioteg 1 epapioteg 2

Stage 1: 1-cyclopropylcyclopropanol solution

To a solution of methylcyclopropanecarboxylate (75 g, 749.1 mmol) in ether (450 mL) was added titanium isopropoxide (IM) (55.3 mL, 187.4 mmol). Ethylmagnesium bromide (1.6 L 1 M, 1.60 mol) was slowly added to the mixture over 2 hours. The addition is exothermic and is controlled by controlling the rate of addition and using a cooling bath. During the addition, the reaction temperature was maintained in the range of 21-26 °C. After the addition, the mixture was stirred for another 2 h at ambient temperature. The mixture was then cooled to -5 °C using an acetone/dry ice bath and slowly quenched with sulfuric acid (970 g 10 95 wt./wt., 990 mmol). The reaction mixture was cooled in a dry ice/acetone bath to maintain the temperature in the reaction vessel below 0 °C during quenching. A gray-purple solid was formed during quenching. After complete addition of aqueous sulfuric acid, the mixture was stirred at 0 °C for 1 hour. The precipitate was filtered through celite using a medium size frit and the precipitate was washed with diethyl ether (900 mL). The filtrate was transferred to a separatory funnel, and the organic phase was washed with brine (1 L), saturated sodium bicarbonate (1 L), and brine (1 L). The organic phase was dried over magnesium sulfate, filtered through celite, and the solvent was evaporated on a rotary evaporator at 100 torr and the water bath was set at 20°C. The crude product was stored at -23 "C overnight and used without further purification. The product, 1-cyclopropylcyclopropanol (61 g, 83 95), was found to contain about 50 95 of solvent (tetrahydrofuran and iIRGONE) and as such was used for next stage. IN NMR (400

MHz, chloroform-a) 6 1.32 (tt, U - 8.2, 5.1 Hu, 1H), 0.71-0.61 (m, 2H), 0.51-0.43 (m, 2H), 0.43-0.33 (m, 2H), 0.23-0.14 (m, 2H).

Stage 2: 1-bromo-1-cyclopropyl-diclopropane

A solution of triphenylphosphine (56.1 g, 213.9 mmol) in dichloromethane (200 mL) was cooled to -10 °C. A solution of bromine (11.0 mL, 214 mmol) in dichloromethane (40 mL) was added, and the reaction mixture was stirred at -10 "C for an additional 15 minutes. Then the reaction mixture was cooled to -30°C and pyridine (3.3 ml, 41 mmol) was added. A solution of 1-cyclopropylcyclopropanol (20.0 g, 204 mmol), pyridine (17.3 ml, 214 mmol) and dichloromethane

Zo (100 mL) while maintaining the temperature from -157°C to -20°C. After 30 min, the addition was complete and the reaction mixture was allowed to gradually warm to room temperature. The reaction mixture was then allowed to stir at 40°C overnight. Then the reaction mixture was cooled to room temperature and quenched with water (100 ml). Then the reaction mixture was stirred for 10 minutes and the phases were separated. The organic phase was successively washed with 1 M hydrochloric acid (102 ml), then with saturated sodium bicarbonate (50 ml), dried over sodium sulfate, filtered and concentrated (30 °C/vacuum in place - 300 torr) to remove most of the dichloromethane. The crude reaction the mixture was subjected to rapid distillation (40 "С/ 20 torr) to remove an additional amount of dichloromethane. The solid residue (RPZRO and product) was reheated and distilled (50-60 "С/20 torr) to obtain 21.5 g (yield 65 9) of 1-bromo-1-cyclopropylcyclopropane in the form of a cloudy colorless liquid. IN NMR (400

MHz, chloroform-a) 56 1.61 (tt, U - 8.2, 5.0 Gu, 1H), 1.07-1.02 (m, 2H), 0.78-0.66 (m, 2H), 0.67-0.51 (m, 2H), 0.35-0.21 (m, 2H).

Stage 3: cyclopropylidenecyclopropane shk

A solution of potassium tert-butoxide (16.7 g, 148.8 mmol) in dimethyl sulfoxide (100 mL) was stirred at room temperature in a 250 mL three-neck round-bottom flask. 1-Bromo-1-cyclopropylcyclopropane (20.0 g, 124.2 mmol) was added dropwise and the reaction immediately turned dark and then brown. The reaction was moderately exothermic (the temperature was maintained from 187C to 22C using an ice water bath). After 10 min the addition was complete. The ice water bath was removed and the reaction mixture was allowed to stir at room temperature. After 90 min, the reaction mixture was distilled in vacuo using flask-to-flask distillation. Distillation took place from 60 "C to 80 "C, from 40 to 100 torr. The distillate slowly collected in the receiver to give 18.2 g (7.3 g of product as

42 wt. 95 solution in tert-ViOH) colorless liquid. The distillate was additionally washed with water (5 x 10 ml). Dichloromethane (4 g) was added, and the mixture was dried over magnesium sulfate, filtered (washing with two additional portions of 3 g of dichloromethane each) to obtain 17.30 g (6.9 g of product in the form of a 39.6 wt. 95 solution in dichloromethane; output 69 95) in the form of a colorless liquid. TN NMR (400 MHz, chloroform-4) b 1.19 (s, 8H). IN NMR confirms the presence of dichloromethane and a small amount of tert-butanol.

Stage 4: ethyl dispiro(2.0.2.1|heptane-7-carboxylate (e) mM.

Rhodium(II) acetate (4.2 g, 9.503 mmol) was added to a solution of cyclopropylidenecyclopropane (49.5 g, 617.8 mmol) in dichloromethane (110 ml) at 0"С under a nitrogen atmosphere. To the mixture at 0"С was added ethyl 2-diazoacetate (106.8 mL, 1.016 mol) using a syringe pump set at an addition rate of 0.02 mL/min (1.2 mL/h). The addition was continuous for 89 hours. The crude reaction mixture was filtered through a layer of silicon dioxide, washing three times with 150 ml of dichloromethane. Volatiles were removed in vacuo to give a crude dark yellow oil, ethyl dispiro|2.0.2.1|heptane-7-carboxylate (100 g, 97 95, containing 2095 of dichloromethane, diethyl(E)-butyl-2-enedioate and diethyl(7 )-butyl-2-enedioate as pollutants), which was used directly in the next stage. NMR (400 MHz, chloroform-4) b 4.13 (k, U - 7.1 Hu, 2H), 2.23 (s, 1H), 1.24 (t, U - 7.1 Hz, ЗН), 1.08-0.93 (m, 4H), 0.90-0.82 (m, 2H), 0.77 (ddd, y - 8.2, 5.0, 3.5 Hz, 2H).

Stage 5: dispiro|2.0.2.1|heptan-7-yl methanol () scha Oto --- schi on

Ethyl dispiro|2.0.2.1|heptane-7-carboxylate (10.77 g, 64 .79 mmol). The mixtures were allowed to gently reflux during the addition and continued to stir at ambient temperature for 1 hour. The reaction mixture was cooled in an ice-water bath and slowly quenched by adding water (8.0 mL, 440 mmol), then sodium hydroxide (8.0 mL 2 M, 16 mmol) and then water (24.0 mL, 1.33 mmol ). The light yellow suspension was filtered through celite and washed with 150 ml of methyl tert-butyl ether three times. The filtrate was concentrated in vacuo,

, giving 8.87 g of a clear oil, dispiro(2.0.2.1|heptan-7-ylmethanol (8.87 g, quantitative yield). 1H NMR (400 MHz, chloroform-4) 5 3.71 (dd, y - 6 ,7, 5.5 Hz, 2H), 1.76-1.65 (m, 1H), 1.46 (t, u - 5.6 Hz, 1H), 0.687 (k, U - 1.9 Gu , 4H), 0.72-0.61 (m, 2H), 0.60--0.50 (m, 2H).

Stage 6: tert-butyl 3-(dispiro|2.0.2.1|heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate

M.,,. Vos and -a

A solution of dispiro(2.0.2.1|heptan-/-ylmethanol (1.36 g, 11.0 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (2.3 g, 12 mmol) and triphenylphosphine (3.2 g, 12 mmol) in tetrahydrofuran (28 mL) was cooled in an ice bath and diisopropylazodicarboxylate (2.4 mL, 12 mmol) was slowly added. The cooling bath was removed and the reaction mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate , dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 0-20 95 ethyl acetate in hexane to give tert-butyl-3-(dispiro|2.0.2.1|)heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate (1.57 g, yield 49 95) as a colorless oil. MO-IER t/2 calc. 290.16306, found 291.3 (M--1)k; Holding time: 0.76 min. (Method of RH A).

Stage 7: 3-(dispiro(2.0.2.1|heptan-7-ylmethoxy)-1H-pyrazole a - dO

A solution of tert-butyl 3-(dispiro|2.0.2.1|heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate (1.57 g, 5.41 mmol) and trifluoroacetic acid (2.2 mL, 29 mmol) ) in dichloromethane (20 ml) was stirred for three hours. Volatile substances were removed in vacuo, the residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated to give 3-(dispiro(2.0.2.1|)heptan-7-ylmethoxy)-1H-pyrazole (0.94 g, yield 91 95) as a pale yellow oil . MO-IER t/7 calc. 190.11061, found 191.1 (M--1)x; Holding time: 0.52 min. (Method of RH A).

Stage 8: ethyl-2-chloro-6-(3-(dispiro(2.0.2.1|heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate (e) with M. and ol x ol 6 -5 - - - -zhz- M shcha that - 0-57 M" oi

SI M s d-

A mixture of 3-(dispiro|2.0.2.1|heptan-7-ylmethoxy)-1H-pyrazole (0.94 g, 4.9 mmol), ethyl 2,6-dichloropyridine-3-carboxylate (1.15 g, 5 .23 mmol), potassium carbonate (0.83 g, 6.0 mmol) and 1,4-diazabicyclo|2.2.2|octane (0.12 g, 11 mmol) in dimethylsulfoxide (16 mL) were stirred for 24 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saline and water, dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on a column with silica gel, eluting with a gradient from 0 to 20 95 ethyl acetate in hexane, to obtain ethyl 2-chloro-6-(3-(dispiro|2.0.2.1|)heptan-7-ylmethoxy)-1H-pyrazole -1 yl)nicotinate (1.39 g, yield 7595) as a colorless solid. 1H NMR (400 MHz, Spiogoitogit-4) b 8.36 (y, U - 2.8 Hz, 1H), 8.27 (y,

U - 8.5 Hz, 1H), 7.72 (a, U - 8.5 Hz, 1H), 5.96 (a, U - 2.9 Hz, 1H), 4.41 (d, U - 7.1 Hz, 2H), 4.30 (a, 9 - 7.0 Hz, 2H), 1.94 (Her, U - 7.0 Gu, 1H), 1.42 (9 - 7.1 Hz, ZN), 1.02-0.89 (t, 4H), 0.75-0.65 (t, 2H), 0.65-0.53 ( t, 2H). MO-IER t/2 calc. 373.11932, found 374.2 (M--1)k; Holding time: 0.87 min. (Method of RH A).

Stage 9: 2-chloro-6-3-(dispiro(2.0.2.1|heptan-7-ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid c) c) tova o - Mb soi -a ke

A solution of ethyl /2-chloro-6-(3-(dispiro(2.0.2.1|heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate (1.39 g, 3.72 mmol) and sodium hydroxide ( 7.5 mL of a 1 M solution, 7.5 mmol) in tetrahydrofuran (6 mL) and ethanol (3 mL) was stirred for 90 min. Volatiles were removed under vacuum and water was added. The reaction mixture was cooled in an ice bath and hydrogen chloride was slowly added

Zo acid (7.5 ml of 1 M solution, 7.5 mmol). The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saline, dried over sodium sulfate, filtered and evaporated to obtain 2-chloro-6-|3-(dispiro|2.0.2.1|heptan-7-ylmethoxy)pyrazol-1-yl|pyridin-3- carboxylic acid (1.16 g, yield 82 95) as a colorless solid. 1H NMR (400 MHz, DMSO-ab) b 8.41 (a, U - 2.9 Hz, 1H), 8.38 (j, U - 8.4 Hz, 1H), 7.73 (a, - 8.4 Hz, 1H), 6.19 (a, U - 2.68 Hz, 1H), 4.27 (a, 9 - 7.0 Hz, 2H), 1.93 (Her, U - 7.0 Hz, 1H), 0.97 - 0.79 (t, 4H), 0.76 - 0.66 (t, 2H), 0.65 - 0.56 (t, 2H). MO-IER t/2 calc. 345.088, found 346.1 (MAT) same; Holding time: 0.73 min. (Method of RH A).

Stage 10: tert-butyl 4-I3-C6-C2-chloro-6-3-(dispiro(2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2 -pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (c) oo 96o och oo Zhle ony I: Xia 0-47 M. ote Y vo Vosm ka MN

MN neo

2-chloro-6-I(3-(dispiro|2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (300 mg , 0.8676 mmol) and anhydrous tetrahydrofuran (4 ml). Carbonyl diimidazole (214 mg, 1.320 mmol) was added and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 h. In a separate vessel with a volume of 20 ml, which was maintained in a nitrogen atmosphere, a solution of tert-butyl-2,2-dimethyl-4-I3-((6-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-i-carboxylate ( 358 mg 0.678 mmol) in anhydrous tetrahydrofuran (2 mL) and added via syringe to the activated ester solution.

1,8-diazabicyclo(5.4.0)undec-7-ene (0.29 mL, 1.939 mmol) was added and the mixture was stirred at room temperature for 19 hours. The solvent was evaporated and the residue was treated with water (50 mL), ethyl acetate (50 mL) and hydrochloric acid (1 mL, 6 M, 6,000 mmol). The two phases were separated. The aqueous phase was further extracted with ethyl acetate (25 ml). The combined organic phases were washed with saline (30 ml), dried over sodium sulfate, and the solvents were evaporated. The product was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100 95 over 30 minutes) in hexane. Pure fractions were collected and the solvents were evaporated to give 408 mg of product as a solid foam.

LCMS showed that the material contained 6 95 parent carboxylic acid. The product was purified a second time using the same method to give /tert-butyl-4-N3-C(6-Ce-chloro-6-(3-(dispiro|(2.0.2.1|)heptan-7-ylmethoxy)pyrazol- 1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (364 mg, 57 95) in the form of a colorless resin. MO-IER t/2 calc. 739 ,2919, found 740.3 (M'-1) zhk; Retention time: 2.45 min. (Method RH

IN).

Stage 11: 2-chloro-M-((6-(3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-pyridyl|sulfonyl|-6-(3- (dispiro|(2.0.2.1 |)heptan-7-ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt)

CO. SO li V ak y om ts y de oy wa oy

VosM NM "NS

Tert-butyl 4-I3-C(6-C2-chloro-6-|(3- (dispiro|(2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl) was introduced into a round-bottomed flask with a volume of 100 ml |Ipyridine-3-carbonyl|Isulfamoyl|-2- pyridylIamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (364 mg, 0.4917 mmol), dichloromethane (5 mL) and hydrochloric acid (0.5 mL 4 M, 2,000 mmol) (4 M in dioxane). The vial was capped and stirred at room temperature for 5 h. An additional amount of hydrochloric acid (0.5 mL 4 M, 2,000 mmol) was added and the mixture was stirred for an additional hour.

Volatile substances were removed on a rotary evaporator under vacuum at room temperature.

The residue was triturated with dichloromethane/hexane and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in a vacuum gives 2-chloro-M-I((6-I3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-pyridyl|sulfonyl|-6-IZ-(dispiro|2.0.2.1| Heptan-7-ylmethoxy)pyrazol-1-yl|pyridin-3-carboxamide (dihydrochloride salt) (325 mg, 93 95) as a white solid. MO-IER t/2 calcd 639.23944, found 640.3 (M'-1)g Retention time: 1.58 min (Method RH B).

Stage 12: 8-13-("I(dispiro(2.0.2.1|)heptan-7-yllomethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 106) and 8-(3-S-dispiro|2.0.2.1|heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23 -pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 107)

at 968

CO

Nm

Am M to A - 6 -zhyu o ai nyu -sh8-7 Y om d- y oo

From 5

Fa: 0. Fe: and ra res

МН МН epapioteg 1 epapboteg 2

2-chloro-M-I(6-I3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-pyridyl|sulfonyl| /-6-

3-(dispiro|2.0.2.1|heptan-7-ylmethoxy)pyrazol-1-yl|pyridin-3-carboxamide (dihydrochloride salt) (325 mg, 0.4557 mmol), anhydrous MMR (3 mL), potassium carbonate ( 269 mg, 1.946 mmol) (ground in a mortar) and cesium fluoride (70 mg, 0.4608 mmol). The mixture was vigorously stirred at 140 C in a nitrogen atmosphere for 15 h. The mixture was diluted with water (20 ml) and acidified by slowly adding hydrochloric acid (500 μl 6 M, 3,000 mmol, final pH - 4-5). The resulting solid was filtered and briefly air-dried. The solid was dissolved in dichloromethane/ethyl acetate (total volume 75 mL), dried over sodium sulfate, filtered, and concentrated to give a solution that was purified by flash chromatography on silica gel using a methanol gradient (from 0 to 595 in 30 min) in dichloromethane. Evaporation of solvents gives racemic 8-I3-(«(dispiro(2.0.2.1|heptan-7-ylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18 ,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 105) (102 mg, 36 95) in the form of a white solid. IN NMR (400 MHz, DMOO-av) b 12.51 (5, 1H), 68.20 (a, y - 2.8 Hz, 1H), 7.81 (a, 9U - 8.2 Gu, 1H) . U - 8.5 Hz, 1H), 6.11 (a, U 2 2.7 Hz, 1H), 4.24 (a, U - 7.0 Hz, 2H), 4.0-3.85 (t, 1H), 3.15 (Bg 5, 1H), 2.95 (rg a, U - 13.3 Hz, 1H), 2.75-2.65 (t, 1H), 2.12 (Bg 5, 1H), 1.91 (i, U - 7.0 Hz, 1H), 1.89 20. - 1.67 (t, 2H ), 1.67 - 1.41 (t, 9H), 1.37 - 1.26 (t, 1H), 0.97 - 0.81 (t, 4H), 0.74 - 0.65 (t, 2H), 0.66 - 0.53 (t, 2H). MO-IER t/: calcd. 603.26276, found 604.2 (M.-1) t; Retention time: 2.26 min (RC Method B). This racemic material (97 mg) was subjected to chiral separation of NKR (Spi column HAIRak A5-H (250 X 10 mm), 5 µm, 35 o C, mobile phase 38 95 acetonitrile:methanol (90:10 without modifier), 62 95 carbon dioxide, 10 ml/min, 24 mg/ml in acetonitrile: methanol (90:10 without modifier), injection volume 70 μl, 100 bar) The first eluted enantiomer was collected, the solvents were evaporated, and the residue was triturated in dichloromethane/hexane.

Evaporation gives 8-(3-((dispiro|2.0.2.1|heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23 -pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (enantiomer 1) (compound 106) ( 46 mg, 32 90).YAN NMR (400 MHz, DMSO-ab6) b

Zo 12.50 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 7.81 (a, - 8.2 Hz, 1H), 7.57 (I, U - 7.8 Gu, 1H), 7.054549, 7.2

Hz, 1H), 6.98 (Bgoaa a, U - 7.3 Hz, 1H), 6.91 (a, U - 8.2 Hz, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.10 (a, - 2.1 Gu, 1H), 4.23 (a, U - 7.0 Hz, 2H), 3.99 - 3.82 (t, 1H), 3.15 (Bg 5, 1H), 2.95 (Bg a, U - 13.4 Gu, 1H), 2.80 - 2.62 (t . , 0.98 - 0.81 (t, 4H), 0.75 - 0.64 (t, 2H), 0.66 - 0.53 (t, 2H). MO-IER p/z: calc. 603.26276, found 604.3 (Ma-1)j; Holding time: 2.27 min. (Method of RH E). The second enantiomer for elution was collected, the solvents were evaporated and the residue was triturated in dichloromethane/hexanes. Evaporation gives 8-I3-(Idispiro|2.0.2.1|heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (compound 107) (43 mg, 31 95). 1 N NMR (400

MHC, dimethylsulfoxide-a6) b 12.50 (5, 1H), 8.20 (a, 9 - 2.8 Hz, 1H), 7.81 (a, U - 8.2 Hz, 1H), 7.57 (i, 9 - 7.9 Gu, 1H), 7.05 (y, U - 7.2 Hu, 1H), 6.98 (bBgoai a, U - 8.5 Hu, 1H), 6.91 (a, U - 8.2 Hu, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.10 (a, 9 - 2.7 Hz, 1H), 4.23 (y, U - 7.0 Hz, 2H), 4.02 - 3.82 (t, 1H), 3.23 - 3.06 (t, 1H), 2.95 (Bga, y - 13.1 Hz, 1H), 2.80 - 2.62 (t, 1H), 2.12 (Bg 5, 1H), 1.91 (1, 9 - 7.0 Hz, 1H), 1.88 - 1.68 (t, 2H), 1.68 - 1.42 (t, 9H), 1.39 - 1.24 (t, 1H), 0.96 - 0.81 (t, 4H), 0.74 - 0.64 (t, 2H), 0.64 - 0.53 (t, 2H). MO-IER t/: calc. 603.26276, found 604.3 (M--1) k; Retention time: 2.27 min (method RH B).

Example 28: Preparation of 12,12,20-trimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 . 114) and 12,12,20-trimethyl-8-(3- (2-P-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11, 18,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (enantiomer 2) ( Compound 115) teh I tyh shk dosh vno ber

SI "SI" lo at 8 o'clock

AH, I 71. ZierZ av ano vyvr4 (e) Mah si M

NM du gode) BM zh nad Zhe y Go SEz Y 2 | I Zer5 Mezon verb o h vosm mi ona -60Й2KW

Si 00 Oct 8- U

SEz o o SEz o o o 5-5 M ss yin Me zh 5-5 Moss yin Me o "Her d-

SEZ o oo SEZ o 9 SEZ o oo shodo alley nvluvovko

Lem M Mach Me ---» lD- 2 Mach v L- 2 Ma e sha -Yul/v oi " I /n " oi " ЕЮ " epapioteg 1 epapioteg 2

Stage 1: 2-chloro-6-iodo-3-methylpyridine which is

M. and Me M. and Me

SI SI

A solution of 2-(dimethylamino)ethanol (13.02 g, 14.7 mL, 146.1 mmol) in hexane (120 mL) was cooled to -5 °C and treated with butyllithium (132 mL of 2.5 M in hexane, 330, 0 mmol) over a period of 45 minutes. The flask was kept at a temperature from -5 to 0"C for 1 hour, then cooled to -78"C. A solution of 2-chloro-3-methylpyridine (7 g, 54 .87 mmol) in hexane (70 ml and 10 ml wash) and the mixture was stirred at -78 "C for 2 hours. A solution of iodine (56 g, 11.56 mL, 220.6 mmol) in tetrahydrofuran (200 mL) was added dropwise over approximately 1 h and the reaction mixture was allowed to gradually warm to room temperature overnight. The mixture was cooled in an ice bath and slowly quenched with water (250 ml). It was transferred to a 1000 ml separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 250 mL), and the organic layers were combined, washed with water containing 10 95 aqueous sodium thiosulfate (the organic layer became clear), water (200 mL), and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel on a 220 g column, eluting with 095 to 1595 ethyl acetate in heptanes, obtaining pure and mixed fractions. The mixed fractions were further purified by chromatography on silica gel on a 120 g column, eluting from 0 90 to 1595 ethyl acetate in heptane, then triturated in heptane, dried and combined with the previous pure fractions from the first column with silica gel to obtain 2-chloro-6-iodo -3-methylpyridine (9.7 g, 68 Fo) as a pale yellow solid. TN NMR (300 MHz, SOSIZ) ppt 2.32 (5, ZH), 7.18 (a, 9-76 Hz, 1H), 7.56 (j, 9U-7.6 Hz, 1H). MO-IER p/z: calc. 252.9155, found 254.0 (M--1); Holding time:

From 2.71 min. (The method of RH N).

Stage 2: 2-ethylhexyl 3-((b-chloro-5-methyl-2-pyridyl)sulfanyl|propanoate

! xx AH at 5 o'clock mo and sb: 72 i 715.

SI Go) si

A solution of 2-chloro-6-iodo-3-methylpyridine (15.4 g, 60.76 mmol) and diisopropylethylamine (15.73 g, 21.2 mL, 121.7 mmol) in toluene (300 mL) was degassed by bubbling nitrogen within 10 min.

Tris(dibenzylideneacetone)dipalladium (0) (1.7 g, 1.856 mmol), xanthophos (2.1 g, 3.629 mmol) and 2-ethylhexyl-3-sulfanylpropanoate (14.6 g, 66.86 mmol) were added and the mixture heated at 110 C overnight. The residue was concentrated under reduced pressure and purified by chromatography on silica gel on a 220 g column, eluting with 0 95 to 20 95 ethyl acetate in heptanes, to obtain 2-ethylhexyl-3-((b-chloro-5-methyl-2-pyridyl)sulfanyl| propanoate (15.8 g, 76 95) in the form of a yellow oil LN NMR (300 MHz, SOSIS) ppt 0.88 (I, 9-7.3 Gu, 6H), 1.20-1.44 (t, 9H), 2.30 (v, ЗН) . 7.9 Hz, 1N).

MO-ER t/2 calc. 343.912, found 344.2 (M.-1)k; Holding time: 2.76 min. (Method РХ 1).

Stage 3: 2-ethylhexyl 3-((b-chloro-5-methyl-2-pyridyl)sulfonyl|propanoate

SI SI

M-chloroperbenzoic acid (21.6 g, 96.38 mmol) was slowly added to a solution of 2-ethylhexyl-3-((b-chloro-5-methyl-2-pyridyl)sulfanyl|propanoate (15.8 g, 45, 4 mmol) in dichloromethane (135 mL) at room temperature. The mixture was stirred at this temperature for 5 hours. Ethyl acetate (500 mL) was added and the resulting mixture was washed with saturated sodium bicarbonate solution (250 mL), then with 0.5 M sodium hydroxide solution ( 2 x 250 ml).

The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The residue was purified by chromatography on silica gel on a 220 g column, eluting from 0 905 to 40 95 ethyl acetate in heptanes, obtaining 2-ethylhexyl-3-|(b-chloro-5-methyl-2-pyridyl)sulfonyl|propanoate (12.36 g, 72 9o) in the form of a transparent oil. "IN NMR (300 MHz, SOSIZ) ppt 0.82-0.94 (t, 6H), 1.20-1.41 (t, OH), 2.49 (v, ЗН), 2.78-2.89 (t, 2H), 3.66-3.76 (t, 2H), 4.01 (aa, 9U-6.0, 1.9 Hz, 2H), 7.77-7.84 (t, 1H), 7.89-7.96 (t, 1H). MO-IER t/2 calculated 375.911, found 376.1 ( M--1) zhk; Retention time: 2.43 min. (Method RH I).

Stage 4: b-chloro-5-methyl-pyridine-2-sulfonamide. 0 NM moe (Fe) M 2 6662 M 2

SI SI

Sodium methoxide (7.1 g, 131.4 mmol) was added to a solution of 2-ethylhexyl-3-|(b-chloro-5-methyl-2-pyridyl)sulfonyl|propanoate (12.36 g, 32.88 mmol) in tetrahydrofuran (100 ml) and methanol

Zo (35 ml) at room temperature. The reaction mixture was stirred for 4 h, then the mixture was concentrated under reduced pressure to obtain a white solid intermediate. To this intermediate was added hydroxylamine-O-sulfonic acid (7.4 g, 65.43 mmol) and sodium acetate (8.1 g, 98.74 mmol) in water (240 mL) at 0 °C. The mixture was stirred at at room temperature overnight and then extracted with ethyl acetate (2 x 300 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 120 g column, eluting with 20 90 to 80 95 ethyl acetate in heptanes to give b-chloro-5-methylpyridine-2-sulfonamide (5.9 g, 86 95) as a white solid. TN NMR (300 MHz, DMSO-ab) mp 2.40 (5, ZN), 7.59 ( 5, 2H), 7.82 (a, 9U-7.6 Gu, 1H), 8.04 (a, 9U-7.6 Hz, 1H). MO-IER t/: calculated 206.65, found 207.1 (Ma1)k; Retention time: 1.44 min (Method RH I).

Step 5: tert-butyl 2,2-dimethyl-4-N3-(3-methyl-6-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate:

Fe oo Nam vm? | and on | and, She Me vn

M a 8-- MN

SI VosM Fr

In a 5 mL microwavable vial b-chloro-5-methylpyridine-2-sulfonamide (460 mg, 2.226 mmol), tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (380 mg, 1.482 mmol) and diisopropylethylamine (1.3 mL, 7.163 mmol) were dissolved in n-ViOH (3 mL). The vessel was hermetically sealed and stirred at 160°C overnight. The mixture was filtered and directly purified by preparative reversed-phase HPLC (C18): a gradient of 1-99 95 acetonitrile in water/hydrochloric acid modifier (15 min) to give tert-butyl-2, 2-dimethyl-4-I3-((3-methyl-6-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (130 mg, 21 95). MO-IER t/2 cal. 426.23007 , found 427.36 (M--1) zk; Retention time: 1.36 min. (Method

RK B).

Stage 6: tert-butyl 4-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-3 -methyl-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate: se o du SEZ ooo

Ku | he mm m XX nok,

M. 2 i e o-«a M OM O SI Me 0-5 more MN ha MN

2-Chloro-6-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (345 mg, 0.9182 mmol) in a 20 ml microwaveable vial and carbonyl diimidazole (150 mg, 0.9251 mmol) was pumped/flushed with nitrogen (3 times).

Dry tetrahydrofuran (4 ml) was added and the mixture was stirred for 90 minutes at 50 "C. then a solution of tert-butyl-2,2-dimethyl-4-(3-(3-methyl-6-sulfamoyl-2-pyridyl)amino| propyl|pyrrolidine-1-carboxylate (260 mg, 0.095 mmol) and 1,8-diazabicyclo/5.4.O)undec-7-ene (228 μL, 1.525 mmol) in tetrahydrofuran (4 mL) was added and the mixture was stirred at 50 C overnight. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution and then with brine. The organic extract was dried, evaporated and purified by reversed-phase preparative HPLC (C 18): gradient acetonitrile in water/hydrochloric acid buffer 1-99 95 (15 min) to obtain tert-butyl-4-I3-(6-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl| -

Z-methyl-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (290 mg, 6195) MO-IER t/2 calc. 783.27924, found 784.31 (M.-1)k; Retention time: 2.42 min (method RH B).

Stage 7. 2-chloro-M-((6-(3-(5,5-dimethylpyrrolidin-3-yl/propylamino|-5-methyl-2-

Zo pyridyl|sulfonyl|-6-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide) (hydrochloride salt):

SEz o oo SEz o Chu; cheap shen

М - М. М. 2 М 2 / и шко Ме .- ЖИККмУ 0-й 7М МОСС Me ше МН в МН -о- NS t

Solution / tert-butyl-4-I3-C(6-Ce-chloro-6-I(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl |-3-methyl-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (290 mg, 0.3698 mmol) in dichloromethane (6 mL) was treated with hydrochloric acid (4 M in dioxane) (3 mL 4 M , 12.00 mmol) and stirred at room temperature for 30 min. The mixture was evaporated to dryness under reduced pressure to obtain 2-chloro-M-I(6-(3-(5,5- dimethylpyrrolidin-3-yl/upropylamino|- 5-methyl-2-pyridyl|sulfonyl|-6-I(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (hydrochloride salt)) (265 mg, 99 95 ).The product was used in the next stage without additional purification.

Stage 8: 12,12,20-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione:

SE se zu SEz o oo and M 5 5

Ku | N | y M y o- My s Go M ee: o pcs. (and

God and God "NS

In a 5 ml vial for a microwave oven, a mixture of 2-chloro-M-I((6-(3-(5,5-dimethylpyrrolidin-3-yl)upropylamino|-5-methyl-2-pyridyl|sulfonyl|-6-I (3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (hydrochloride "salt) (265 mg), potassium carbonate (260 mg, 1.881 mmol), cesium fluoride (87 mg 0.5727 mmol) and 4A M5 (300 mg) were pumped/backfilled with nitrogen (3 times). Dimethyl sulfoxide (6 mL) was added and the mixture was stirred at 140 °C for 16 h. The reaction mixture was filtered and purified by preparative reverse-phase HPLC phase (C18): a gradient of 1-99 95 acetonitrile in water/modifier hydrochloric acid (15 min) to obtain 12,12,20-trimethyl-8-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy)- 1 H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23-pentaaztetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6, 68,19,21-hexane-2,2,4-trione (100 mg, 42,905). IER-MS tp/2 calcd 647.2502, found 648.31 (M--1) k.

Stage 9: 12,12,20-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 114) and 12,12,20-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11, 18,23- pentaazatetracyclol17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 2) ( Compound 115)

SEZ o 9 SEZ o o SEZ o o o poshov ni voron vovio gli ay a I Me u a and YAMmei i a cha 2 ZMme sha og sha Lv na Lv epapioteg 1 epapioteg 2

Racemic 12,12,20-trimethyl-8-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab6-thia-3,9,11,18,23 -pentaazatetracyclo!17.3.1.111,14.05,10|tetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (100 mg, 0.07052 mmol) was subjected to chiral separation using NKR chromatography using SpigaIRak AB-N (250 x 10 mm, particle size 5 μm) with a mobile phase of 18 95 methanol (20 mM MNH)/82 95 carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl of a 24 mg/ml solution in methanol/dimethyl sulfoxide (90:10)) with obtaining as the first eluted enantiomer 12,12,20-trimethyl-8-(3-12-(1-

Zo (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)tetracose-1(23 ),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (compound 114) (25.8 mg, 10 95); IN NMR (400 MHz, Spiogoitogt-4) b 8.19 (a, 9 - 2.8

Gu, 1H), 8.08 (y, U - 8.4 Gu, 1H), 7.51 (a, 9 - 7.3 Hz, 1H), 7.42 (y, 9. - 7.3 Hz, 1H), 7.24-7.27 (t, 1H) , 5.90 (a, U - 2.8 Hz, 1H), 4.56 (5, 1H), 4.39 (I, U - 7.2 Hz, 2H), 3.93 (5, 1H), 3.44 - 3.32 (t, 1H), 3.23 ( a, U - 19.68 Hz, 1H), 3.06 (I, U - 9.3 Hz, 1H), 2.72 - 2.53 (t, 1H), 2.14 (5, ЗН), 2.09, 9 - 7.2 Hz, ЗН), 1.25 ( 5, 2H), 1.05 - 0.99 (t, 2H), 0.81 (aa, U - 12.6, 6.6 Hz, 1H), 0.74 (I, U - 3.1 Hz, 2H), Two methyl groups and one CH overlap with residual water; MO-IER t/7 calc. 647.2502, found 648.34 (Ma1)-4; Holding time: 2.25 min. (Method LC A) and as the second eluted enantiomer 12,12,20-trimethyl-8-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia -3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21- hexane-2,2,4- trione (enantiomer 2) (compound 115) (24.7 mg, 25 95); IN NMR (400 MHz, Spiogoitogt-a) b 8.19 (a, Y - 2.68 Hz, 1H), 8.09 (a, Y - 8.4 Hz, 1H), 7.52 (a, y - 7.3 Hz, 1H), 7.43 (9 , 9 - 7.4 Gu, 1Hn), 7.28 (5, 1H), 5.91 (a, U - 2.68 Hz, 1H), 4.58 (a, U - 8.1 Hz, 1H), 4.39 (1.7 - 7.2 Hz, 2H ), 3.97 (a, 9 2 5.8

Gu, 1H), 3.43 - 3.31 (t, 1H), 3.28 - 3.15 (t, 1H), 3.06 (y, U - 9.8 Hz, 1H), 2.65 (y, 9 - 3.6 Hz, 1H), 2.14 (5 . 3.2 Hz, 2N). Two Me groups and one CH overlap with residual water; MO-IER t/72 calc. 647.2502, found 648.31 (M.-1)khk; Retention time: 0.85 min (method RH A).

Example 29: Preparation of 8-I3-(Idispiro|2.0.2.1|)heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,19, 21-pentaazatetracyclo!18.2.2.111,14.05,10|pentacose-

1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 120) and 8-I3- (dispiro(2.0.2.1|heptane-7 -ilumethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23), 5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 121)

I hear; Zier1

Vos-M I am | 7 - to chu

ХИЙ -8 s n І m. uva n fi

And Jafg Son Ver and Mike; M'SMNO viewers

AND

Vos oo -Z 5-0 smo M mn Zivr4 "gne ny 7 oo battle 75 75 i Dou and BD leads epapyoteg 1 epapyoteg 2

Stage 1: tert-butyl-2,2-dimethyl-4-(4-(5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate oo B

МН 8. Nam

Vos--M i Nm CHO shk

M SI Vos. M MN skin

Tert-butyl-4-(4-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.33 g, 4.918 mmol), b-chloropyridine-3-sulfonamide was charged into a round-bottom flask with a volume of 100 ml under a nitrogen atmosphere (945 mg, 4.906 mmol), anhydrous dimethyl sulfoxide (15 mL), and potassium carbonate (695 mg, 5.029 mmol) (just ground in a mortar), and the mixture was stirred at 100 C for 20 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 ml) and poured into a saturated aqueous solution of ammonium chloride (50 ml). The two phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL), and the combined extracts were washed with brine (40 mL). After drying over sodium sulfate and evaporation, the residue was purified by flash chromatography on silica gel (80 g column) using a gradient of ethyl acetate (0 to 100 95 over 30 minutes) in hexane. Evaporation of the solvents gives tert-butyl-2,2-dimethyl-4-

I4-Co5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-i-carboxylate (1.165 g, 5695) as an off-white solid foam. MO-IER t/2 calc. 426.23007, found 427.3 (Ma1)k; Holding time: 1.4 min. (Method of RH B).

Stage 2: tert-butyl 4-N4-(5-C2-chloro-6-3-(dispiro(2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|- 2-pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate in year) -Z sr Nam SU o-o ke M smn

B zma to shi - uh

Vos

2-chloro-6-I(3-(dispiro|2.0.2.1|)heptan-7-ylmethoxy)irazol-1-yl|Ipyridine-3-carboxylic acid (355 mg , 1.027 mmol) and anhydrous tetrahydrofuran (5 ml). Carbonyl diimidazole (183 mg, 1.129 mmol) was added and the mixture was stirred under nitrogen at room temperature for 3.5 h. In a separate vessel with a volume of 20 ml, maintained in a nitrogen atmosphere, a solution of tert-butyl-2,2-dimethyl-4-I4-((5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-i-carboxylate (438 mg, 1.027 mmol) in anhydrous tetrahydrofuran (2.5 mL) was prepared and added via syringe to a solution of the activated ester. stirred at room temperature for 19 h. The solvent was evaporated and the residue was treated with water (50 mL), ethyl acetate (50 mL), and hydrochloric acid (1 mL, 6 M, 6,000 mmol). The two phases were separated. The aqueous phase was further extracted with ethyl acetate (25 The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, and the solvents were evaporated. The product was dissolved in dichloromethane and purified by flash chromatography on silica gel (40 g gold column) using a gradient of ethyl acetate (0 to 100 95 for 30 minutes) in hexane.The pure product fractions were collected and the solvents were evaporated to give tert-butyl -4-I4-C(5-C2-chloro-6-3-(dispiro(2.0.2.1|heptan-7-ylmethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|butyl |-2,2-dimethylpyrrolidine-1-carboxylate (467 mg, 60 95) as a white solid. MO-IER Ip/2 calc. 753.30756, found 754.3 (Ma1) xx; Holding time: 2.34 min. (Method of RH B).

Stage 3: 2-chloro-N-(6-(4-(5,5-dimethylpyrrolidin-3-yl)butylamine|-3-pyridyl|sulfonyl|-6-(3-(dispiro(2.0.2.1|)heptane -7-ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt). o oo o ode) - M» d mb xx

KA SU

B- zmo MY plural 5 - ZM o MY plural «gne no o

Vos

Tert-butyl-4-(4-(5-(C2-chloro-6-|(3-(dispiro|2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl) was loaded into a 100 ml round-bottom flask. Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylyamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (467 mg, 0.6191 mmol), dichloromethane (6 mL) and hydrochloric acid (0.63 mL, 4 M , 2.520 mmol) (4M in dioxane). The reaction was stirred at room temperature for 3 h. An additional amount of hydrochloric acid (0.5 mL 4 M, 2.000 mmol) was added and the mixture was stirred for an additional hour. Volatiles were removed

With evaporation under vacuum. The residue was triturated with dichloromethane/hexane and the solvents were evaporated. This operation was repeated until a white solid was obtained. Drying in vacuum gives 2-chloro-M-I(6-(4-(5,5-dimethylpyrrolidin-3-yl/butylamine|-3-pyridyl|sulfonyl|-6-(3- (dispiro|(2.0.2.1 |)heptan-7-ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (420 mg, 93 95) in the form of a white solid. The product was used in the next step without further purification. MSOS-IER t/ 2 calcd 653.2551, found 654.3 (M--1)g Retention time: 1.58 min (Method RH B).

Stage 4: 8-I3-«(I(dispiro(2.0.2.1|heptan-7-yl methoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19 ,21-pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 120) and 8-13-(dispiro|2.0.2.1|heptan-7-yllomethoxy)-1H-pyrazol-1-yl|I-12,12-dimethyl-2A6-thia-3,9,11,19,21- pentaazatetracycloyi18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 121)

ooo9o

ML

Meme M | with. | M smn o "gne ni oo96o oo6o

M y y m" y t m" y

AK. Feb epapboteg 1 epapioteg 2

2-chloro-M-(6-(4-(5,5-dimethylpyrrolidin-3-yl)butylamine|-3-pyridyl|sulfonyl|- 6-

3-(dispiro|2.0.2.1|heptan-7-ylmethoxy)pyrazol-1-yl|pyridin-3-carboxamide (dihydrochloride salt) (420 mg, 0.5776 mmol), anhydrous MMR (5 mL), potassium carbonate ( 343 mg, 2.482 mmol) (ground in a mortar) and cesium fluoride (89 mg, 0.5859 mmol). The mixture was intensively stirred in a dry bath at 145 C in a nitrogen atmosphere for 13 hours, then at 165 "C for 8 hours. After cooling to room temperature, the mixture was diluted with water (30 ml) and acidified by slowly adding hydrochloric acid (600 μl b M, 3,600 mmol) (final pH - 4-5).

The resulting solid was filtered and briefly air-dried. The solid was dissolved in dichloromethane/ethyl acetate (total volume 50 mL), dried over sodium sulfate, filtered, and concentrated to obtain a solution that was purified by flash chromatography on silica gel (24 g gold column) using a methanol gradient (from 0 to 5 95 for 30 min) in dichloromethane. Evaporation of the solvents, trituration in dichloromethane/hexanes, and evaporation of the solvents again gave the racemic product (79 mg, 22 95) as a white solid. This racemic material was subjected to chiral NCR chromatography (SpigaiRak AB-N (250 X 10 mm), column 5 μM; mobile phase 3895 acetonitrile/methanol (90:10, without modifier), 6295 carbon dioxide, 10 ml/min; concentration 24 mg/ml in acetonitrile/methanol/dimethylsulfoxide (80:10:10; no modifier); injection volume - 70 μl, 100 bar) The first eluted enantiomer was 8-I3-(/dispiro(2.0.2.1|heptane-7 - ilumethoxy)-1H-pyrazol-1-yl|I-12,12-dimethyl-2A6-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23) ,5,7,9,20(24) 21-hexane-2,2,4-trione (enantiomer 1) (Compound 120) (25 mg, 14 95), white solid. IN NMR (400 MHz, DMSO- ab) b 12.13 (Bgoaay 5, 1H, exspapdearie Bu 02090), 8.50 (horn 5, 1H), 8.17 (a, U 2 2.7 Hz, 1H), 7.88 - 7.70 (t, 2H), 7.34 (Big 5, 1H . exp.), 6.90 (a, U - 8.3 Hz, 1H), 6.57 (ad, U - 9.1 Hz, 1H), 6.10 (a, U - 2.8 Hz, 1H), 4.23 (9, U - 7.0 Hz, 2H), 2.54 (5, 4H), 2.08 (Bg 5, 2H), 1.91 (1, 9 - 7.0 Hz, 1H), 1.73 (y, U - 10.4 Hz, 1H), 1.57-1.53 (t, 9H) , 1.34 - 1.15 (t, 1H), 1.05 (rg 5, 2H), 0.95 - 0.83 (t, 4H), 0.75 - 0.64 (t, 2H), 0.59 (a, U - 9.0 Hz, 2H). MO-IER tp/2 calc. 617.27844, found 618.4 (M--1)x; Holding time: 2.15 min. (Method of RH B). The second eluted enantiomer was 8-I3-(dispiro|2.0.2.1|heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|I-12,12-dimethyl-2A6-thia-3,9,11,19, 21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (enantiomer 2) (Compound 121) (24 mg, 13 95), white solid. 1 H NMR (400 MHz, dimethylsulfoxide-a 6 ) А 12.11 (s, 1H), 8.51 (broad s, 1H), 8.17 (d, U - 2.8 Hu, 1H), 7, 80 (d, U - 8.3 Hz, overlaps with wide s, 2H), 7.33 (wide s, 1H), 6.90 (d, U - 8.3 Hz, 1H), 6.57 (d, U -8.9 Hz, 1H), 6.10 (d, U 2 2.7 Gu, 1H), 4.23 (d, U - 7.0 Hz, 2H), 2.62-2.49 ( m, overlaps with the solvent signal, probably 4H ), 2.08 (broad s, 2H), 1.91 (t, U - 7.0 Hz, 1H), 1.72 (broad s, 1H), 1, 54 (m, 9H), 1.24 (wide s, 1H), 1.05 (wide s, 2H), 0.92-0.82 (m, 4H), 0.75-0.64 (m, 2H), 0.59 (d, U - 9.1 Hz, 2H). MO-IER t/2 calc. 617.27844, found 618.5 (M-1) f; Holding time: 2.15 min. (Method of RH B).

Example 30: Preparation of 8-I3-(Idispiro|2.0.2.1|)heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,19, 24-pentaazatetracycloi|18.3.1.05,10.011,15|hetracose-1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 124) her 8-I3- (dispiro(2.0.2.1|heptan-7-ylomethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5(10),6,68,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 125)

kUd fe) Nam A (9)

Vo, MN and Na GO 5ivr 1 - ON b5er2 an shi shko zv et

E Vos-i| o o o, o oo s m y Zh m? and

MAM Nm vano o M shk Zier Z M M shko

And mine is 733337 and MN

Vos-m «ns m and ooo ooo

Same m Same and m? The same o-4 MM o-4 MTMO M

In va With In va With epapboteg 1 epapioteg 2

Stage 1: tert-butyl 2,2-dimethyl-5-3-Kb-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate de) in what Chui et al.

Vos. 7

M tu nm and M M. and MN

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To a solution of tert-butyl 5-(33-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (500 mg, 1.950 mmol) in N,M-dimethylformamide (5 mL) was added b-fluoropyridine-2-sulfonamide (343 mg, 1.950 mmol), followed by potassium carbonate (808 mg, 5.850 mmol). The flask was closed with a septum and heated at 70 "C in a cylinder with nitrogen in an oil bath for 18 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then was purified by chromatography on silica gel (80-gram column) using a gradient from 100 95 hexanes to 100 95 ethyl acetate to obtain tert-butyl-2,2-dimethyl-5-I3-(b-sulfamoyl-2-pyridyl)amino|propyl| pyrrolidine-1-carboxylate (428 mg, 53 95) in the form of a white foamy solid. , 1H), 6.55 (9, 9 - 8.5 Hz, 1H), 5.51 (5, 1H), 5.05 (5, 2H), 3.90 (5, 1H), 3.57 - 3.42 (t, 1H), 3.32 (0, U - 9.68 Hz, 2H), 1.91 (5, 2H), 1.77 (y, U - 30.5 Hz, 1H), 1.62 (a, U - 2.9 Hz, ЗН), 1.48 (5, 10H), 1.27 (I, U - 3.6 Hz, ZN). MO-IER t/ calc. 412.21442, found 413.25 (M--1)k; Retention time: 0.65 min. (RC method B).

Stage 2: tert-butyl 5-I3-C6-Ce2g-chloro-6-3-(dispiro(2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2 -pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate chu ooo

Ge) NM" tA se s s on M s

V-y m uva i B m'ta 0-y 6-7 M SI MN sh- MN

Vos-m -

2-Chloro-6-I(3-(dispiro|2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (327 mg , 0.9457 mmol) and anhydrous tetrahydrofuran (5 ml). Carbonyldiimidazole (168 mg, 1.036 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 h (complete activation by LCMS aliquots in sec-butylamine). In a separate vessel with a volume of 20 ml, which is maintained in a nitrogen atmosphere, a solution of tert-butyl-2,2-dimethyl-5-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (390 mg, 0.9453 mmol) in anhydrous tetrahydrofuran (2.5 mL) and added via syringe to the activated ester solution. 1,68-diazabicyclo|5.4.Fundec-7-ene (0.32 mL, 2.140 mmol) was added and the mixture was stirred at room temperature for 13 hours. The solvent was evaporated and the residue was treated with water (50 mL), ethyl acetate (50 mL) and hydrochloric acid (1 mL, 6 M, 6,000 mmol). The two phases were separated.

The aqueous phase was further extracted with ethyl acetate (25 ml). The combined organic phases were washed with saline (30 ml), dried over sodium sulfate, and the solvents were evaporated. The product was dissolved in dichloromethane and purified by flash chromatography on silica gel (40 g gold column) using a gradient of ethyl acetate (0 to 100 95 over 30 minutes) in hexane. The pure fractions were collected and the solvents were evaporated to obtain tert-butyl 5-I3-C(6-Ce-chloro-6-(3-(dispiro|2.0.2.1|heptan-7-ylmethoxy)pyrazol-1-yl|pyridin-3 -carbonyl|Isulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-i-carboxylate (435 mg, 6295) as a white solid. MO-IER tp/2 calcd. 739.2919, found 740 ,3 (M.-1)-- Retention time: 2.47 min (method RH B).

Stage 3: 2-chloro-M-(6-(3-(5,5-dimethylpyrrolidin-2-yl)/propylamino|-2-pyridyl|sulfonyl|-6-(3- (dispiro(2.0.2.1|) heptan-7-ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt). ooo ooo9vo

M M/ and m? 5 and m? from 0-7 -- 0-7 that MN in MN

Vos.. in | NM | -2NSI

Tert-butyl-5-I3-(6-(2-chloro-6-|(3- (dispiro|(2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl) was loaded into a 100 ml round-bottomed flask) Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (435 mg, 0.5876 mmol), dichloromethane (6 mL) and hydrochloric acid (0.6 mL 4 M , 2,400 mmol) (4M in dioxane). The reaction was stirred at room temperature for 3 h. An additional amount of hydrochloric acid (500 μl 4 M, 2,000 mmol) was added and the mixture was stirred for an additional hour. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane /hexane and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying under vacuum gives

Zo 2-chloro-M-I(6-(3-(5,5-dimethylpyrrolidin-2-yl)propylamino|-2-pyridyl|sulfonyl|-6-(3- (dispiro|2.0.2.1|heptane-7 -ylmethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (439 mg, 105 95) as a white solid. The product was used in the next step without further purification. MO-IER t/2 calc. 639, 23944, found 640.3 (Ma1) gk, Retention time: 1.7 min (Method RH B).

Stage 4: 8-I3-(I(dispiro(2.0.2.1|)heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19 ,24-pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (enantiomer 1) ( Compound 124) and 8-III-((dispiro|2.0.2.1|heptan-7-ylylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,19 ,24-pentaazatetracycloY18.3.1.05,10.011,15)tetracose-1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (enantiomer 2) ( Compound 125)

ooo

M. and M. and 0-4 7M MO of their MN

NM | "gne oo battle xx m"? хх 5 m?

B a sho i V -A ZO epapioteg 1 epapioteg 2

2-chloro-M-I(6-I3-(5,5-dimethylpyrrolidin-2-yl)propylamino|-2-pyridyl|sulfonyl|- 6-IZ-(dispiro|2.0.2.1|)heptan-7-ylmethoxy)pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) (439 mg, 0.6156 mmol), anhydrous MMR (5 mL), potassium carbonate (410 mg, 2.967 mmol) (ground in a mortar) and cesium fluoride (94.82 mg, 23.04 μL, 0.6242 mmol). The mixture was intensively stirred in a dry bath at 145 "С in a nitrogen atmosphere for 46 hours, then at 155 70 for 14 hours. After cooling to room temperature, the mixture was diluted with water (30 ml) and acidified by slowly adding hydrochloric acid (500 μl b M, 3,000 mmol) (final pH - 4-5). The resulting solid was filtered and briefly dried in air. The solid was dissolved in dichloromethane (total volume 50 ml), dried over sodium sulfate, filtered and concentrated, then purified by flash chromatography on silica gel (4 g column) using a gradient of methanol (0 to 5 95 in 30 min) in dichloromethane.Evaporation of the solvents, trituration in dichloromethane/hexanes, and evaporation of the solvents again gave the expected racemic product as an off-white solid (154 mg, 41 Ob).

The racemic material was subjected to chiral NCR chromatography (SpigaIRak Is column (250 x 21.2 mm), 5 μm, mobile phase 38 95 acetonitrile:methanol (90:10 without modifier), 62 95 carbon dioxide, 70 ml/min, 30 mg /ml in acetonitrile:methanol (90:10 without modifier, injected volume 500 μl, 100 bar) After evaporation of the solvents, the residue was triturated in dichloromethane/hexanes and the solvents were removed. The first eluted enantiomer was 8-(3- (dispiro(2.0.2.1|heptan-7-yl methoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19, 24- pentaazatetracyclo|18.3.1.05,10.011,15)tetracose-1-(23),5(10),6,8,20(24) 21-hexane-2,2,4-trione (enantiomer 1) (Compound 124) (62 mg, 33 95), isolated as a white solid. 1TN NMR (4600 MHz, DMOO-ab) 5 12.70 (Bgoaa 5, 1H), 8.21 (a, U - 2.8 Gu, 1H), 8.00 ( bBgoai 4, U - 8.0 Hz, 1H), 7.58 (aa, U - 8.5, 7.2 Hz, 1H), 7.28 (Big 5, 1H), 7.08 (rg 5, 1H), 7.03 (y, U - 7.2 Gu, 1H), 6.62 (a, 9 - 8.4

Hu, 1H), 6.12 (9, U - 2.8 Hz, 1H), 4.24 (a, 9 - 7.0 Hu, 2H), 3.71 (bg 5, 2H), 3.11 (Bg 5, 1H), 2.00 - 1.80 (t , 3), 1.73 (Run 5, 2H), 1.63 - 1.43 (t, 5H), 1.42 - 1.31 (t, 4H), 1.09 - 0.88 (t, 1H), 0.94 - 0.80 (t,

AN), 0.76 - 0.64 (t, 2H), 0.66 - 0.53 (t, 2H). MO-IER t/2 calc. 603.26276, found 604.3 (Ma1)f; Holding time: 1.95 min. (Method of RH B). The second eluted enantiomer was 8-|3-

Zo (dispiro(2.0.2.1|heptan-7-ylmethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05, 10.011,15)hetracose-1(23),5(10),6,68,20(24),21-hexane-2,2,4-trione (enantiomer 2) (compound 125) (54 mg, 28 95 ), isolated as a white solid. 1 H NMR (400 MHz, dimethylsulfoxide-a 6) b 12.67 (broad c, 1H ), 8.21 (a, U - 2.8 Hz, 1H), 68.00 (bha,

U - 7.1 Hu, 1H), 7.58, 9 - 7.8 Hz, 1H), 7.37 - 7.21 (t, 1H), 7.08 (Bg 5, 1H), 7.03 (y, 9 - 7.1 Hu, 1H), 6.62 (a , 9 - 8.5 Hu, 1H), 6.12 (a, U - 2.8 Hu, 1H), 4.24 (a, 9 - 7.1 Hz, 2H), 3.71 (Brg 5, 2H), 3.10 (Bg 5, 1H), 2.02 - 1.79 (t, ZN), 1.73 (5, 2H), 1.64 - 1.45 (t, 5H), 1.42 - 1.28 (t, 4H), 0.99 (ru 5, 1H), 0.94 - 0.77 (t, 4H), 0.77 - 0.65 (t, 2H), 0.64 - 0.54 (t, 2H). MO-IER tp/2 calc. 603.26276, found 604.3 (MAT) zhk; Retention time: 1.96 min (method RH B).

Example 31: Preparation of /(145)-8-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (diastereomer 1) (Compound 126) and (145)-8 -13-(3,3- dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111,14.05, 10|htetracose-1 (23), 5,7,9,19,21-hexane-2,2,4-trione (diastereomer 2) (Compound 127)

yo Y o To

A O -- nie shcha, ' nie shcha; aiazivegeoteg 1 diaziegeoteg 2

Stage 1: (145)-8-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (diastereomer 1) (Compound 126) and (145)-8- (3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2А6б-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10| hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (diastereomer 2) (Compound 127) o ek 9 o ek DZ o 2 Where

Ul m -o Ul M -o " Ul m ro

Mn chn MN

Jaiaziegeoteg 1 adiaviegeoteg 2 (14 5)-8-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione was subjected to chiral NCR separation (separation (SpigaISe! 0- H (250 X 10 mm), 5 µM column, mobile phase 25 95 acetonitrile/methanol (90:10, no modifier), 75 95 carbon dioxide, 10 ml/min, concentration 24 mg/ml in acetonitrile/methanol (90: 10); injection volume 70 μl, 100 bar).

For pure collected fractions, the solvents were evaporated and the residue triturated in dichloromethane/hexane. The first eluted diastereomer was (145)-8-13-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracyclo 17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (diastereomer 1) (Compound 126) (19 mg, 36 95). IN NMR (400 MHz, DMSO-a6) 5 12.42 (5, 1H), 7.68 (a, U - 8.4 Hu, 1H), 7.62 - 7.46 (t, 2H), 7.03 (a, 9 - 7.0 Hu, 1H) , 6.97 (rgoai 5, 1H), 6.70 (a, 9 - 68.6

Gu, 1H), 4.04 (I, U - 9.3 Hz, 1H), 3.99 - 3.83 (t, 1H), 3.74 (d, U - 10.3, 9.7 Hz, 1H), 3.10 (Bg 5, 1H), 2.94 ( a, U 2 13.5 Hu, 1H), 2.76 - 2.63 (t, 1H), 2.24 (da, 9 - 17.4, 7.7 Hu, 1H), 2.10 (Bg 5, 1H), 1.88 - 1.64 (t, 4H), 1.65 - 1.40 (t, 9H), 1.40 - 1.13 (t, 4H), 0.88 (5, 9H). MO-IER tp/2 calc. 582.2988, found 583.4 (Ma1)-4; retention time: 2.13 min. (Method of RH B). The second eluted diastereomer was (145)-8-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1 (23), 5,7,9,19,21-hexane-2,2,4-trione (diastereomer 2) (Compound 127) (17 mg, 32 95). IN NMR (400 MHz, dimethylsulfoxide-ab) b 12.42 (5, 1H), 7.68 (y, U - 8.5 Hz, 1H), 7.61 - 7.49 (t, 2H), 7.04 (a, 9 - 7.1 Hz, 1H) . 13.3 Hu, 1H), 2.15 - 2.55 (t, 2H), 2.30 - 2.18 (t, 1H), 2.09 (horn 5, 1H), 1.88 - 1.69 (t, ЗН), 1.69 - 1.41 (t, TON), 1.34 - 1.15 (t, 4H), 0.88 (5, 9H). MO-IER t/2 calc. 582.2988, found 583.4 (Ma-1)k; Time

From retention: 2.14 min (method RH B).

Example 32: Preparation of 12,12,22-trimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23-pentaazatetracycloi!17.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 129)

is Zivr 1 she Zerg

Ma ----- | -----

Mu

SI

SI

Oho

NM with no! nach g, otv, viyurz - o-vy mi to vivr4 aa shi sia chi

Ge A E what, c) ? or 8 ee: yiv 2 9 i she 8 that o i MN verb M uva Go i K 2 i Ale -i 2-5 i- (o)

Stage 1: 2-benzylsulfanyl-b6-chloro-3-methyl-pyridine

SI and | SYA. Dr

2,6-dichloro-3-methylpyridine (5.05 g, 31.17 mmol) and phenylmethanethiol (3.871 g, 3.659 mL, 31.17 mmol) were dissolved in tetrahydrofuran (50.50 mL) and sodium tert-butoxide (31.17 ml of 2 M, 62.34 mmol). The reaction mixture was stirred for 16 h and partitioned between water and ethyl acetate. The organic phases were separated, washed with saline solution, dried over sodium sulfate, filtered and evaporated. The crude material was used without additional purification of 2-benzylsulfanyl-b-chloro-3-methylpyridine (7.15 g, 92 95). MO-IER t/: calc. 249.0379, found 250.0 (M--1)xh; Holding time: 0.81 min. (Method of RH A).

Step 2: b6-chloro-3-methyl-pyridine-2-sulfonamide

S. r: shchi

From the question

M: | Swing

SI SI

A biphasic mixture of 2-benzylsulfanyl-b-chloro-3-methylpyridine (7.15 g, 28.63 mmol) in dichloromethane (42.90 mL), water (14.30 mL), and hydrochloric acid (2.863 mL, 1 M, 2.863 mmol) was cooled in an ice bath with salt water (hydrochloric acid was added to avoid delayed exothermic effect when adding SiI2). CI2 (8.119 g, 114.5 mmol) was bubbled through the solution (3 times with an interval of 2 min) for an hour. The reaction was stirred at 0 "C. After 1.5 h, the reaction mixture was added dropwise to a solution of MNAOH cooled in an ice bath (43.01 ml, 28 95 wt./vol., 343.6 mmol). The reaction mixture was heated to room temperature temperature and stirred for 15 minutes. The reaction mixture was partitioned between ethyl acetate (60 mL) and water (20 mL). The organic phases were separated and the aqueous layer was extracted with ethyl acetate (2 X 60 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting solid was triturated with dichloromethane (30 mL) and filtered. The solid was washed with a minimal amount of dichloromethane to give an off-white solid, b-chloro-3-methylpyridine-2-sulfonamide (2.95 g , 50 95). IN NMR (400 MHz, DMSO-46) 5 7.94 (y, U - 8.1, 0.9 Hu, 1H), 7.68 (y, 9 - 8.1 Hz, 1H), 7.63 (5, 2H), 2.55 (5, ZN). MO-IER t/: calculated 205.99167, found 2071 (Ma) k;

Holding time: 0.3 min. (Method of RH A).

Stage C: tert-butyl 2,2-dimethyl-4-3-(5-methyl-6-sulfamoyl-2-

From pyridyl)amino|propyl|pyrrolidine-1-carboxylate

0,,0 nam o o Maiu ng? r. g, rt Mne MN

M: 9-6

OA

- 5-5 c)

In a nitrogen-purged microwave reaction flask was added b-chloro-3-methylpyridine-2-sulfonamide (1.12 g, 5420 mmol), tert-butyl-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1 -carboxylate (1 g, 3.900 mmol)), diisopropylethylamine (2.520 g, 3.396 mL, 19.50 mmol) and n-butanol (11 mL). The vessel was hermetically closed and allowed to stir at 125 "C for 20 hours. The solvent was removed by mass, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, evaporated and purified by chromatography on silica gel (gradient from 0 9o to 85 95 ethyl acetate in hexanes) to obtain tert-butyl-2,2-dimethyl-4-(3-(5-methyl-6-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (360 mg, 22 95). MO -IR t/2 calculated 426.23007, found 427.29 (Ma1)g, retention time: 0.67 min (Method RH A).

Stage 4: tert-butyl 4-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-5 -methyl-2-pyridyliamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

E 9-0 Mo I KE ha

IS

- - o- o- (o) (c) 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (317.1 mg , 0.8439 mmol) and carbonyl diimidazole (136.8 mg, 0.8439 mmol) were combined in anhydrous tetrahydrofuran (8.5 ml) and stirred for 90 min at 50 "C. then tert-butyl-2,2- dimethyl-4-(3-(5-methyl-b6-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (360 mg, 0.8439 mmol) with subsequent addition of 1,8-diazabicycloi5.4. Fundets -7-ene (128.5 mg, 126.2 μl, 0.8439 mmol), and the reaction mixture was heated at 50 °C for 15 hours. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution, and then with brine. Organic the layers were separated, dried over sodium sulfate, filtered and evaporated, then purified over silica gel using a gradient of 100 95 hexanes to 75 95 ethyl acetate in hexane to give tert-butyl-4-(3-(( 6-(2-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyride) yn-3-carbonyl|sulfamoyl|-5-methyl-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (326 mg, 49,965). MSO-IER t/2 calc. 783.27924, found 784.42 (M--1)k; Holding time: 0.89 min. (Method of RH A).

Zo Stage 5: 12,12,22-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11 ,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 129)

b 9 c: 7th

MM ho Kz d V. and 0-7 / 9-7 and Shchi M s | ; M d

MV---202232 o-4 MTM M

JSC Do

Well, c)

Part A: tert-butyl 4-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-5 -methyl-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (186 mg, 0.2372 mmol) was dissolved in dichloromethane (3 ml) and 5 hydrochloric acid (4M in dioxane) was added to the mixture (2, 2 mL, 4 M, 8,800 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and carried directly to the next step.

Part B: Combined material from Part A and potassium carbonate (197 mg, 1.425 mmol), cesium fluoride (60 mg, 0.3950 mmol), 3A molecular sieves, and dimethyl sulfoxide (3 mL) in a nitrogen-purged, capped vial. heated to 140 "C and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by reversed-phase preparative HPLC chromatography using a C18 column and a 30-99 A1-81 gradient (acetonitrile-water and - 5 mM hydrogen chloride acid 30 min, X 2 injection) to obtain 12,12,22-trimethyl-8-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl) as a white solid -2A6b-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2 ,2,4-trione (Compound 129) (53 mg, 34 95). MO-IER t/2 calcd. 647.2502, found 648.31 (Ma1)-; Retention time: 2.29 min. (RC method IN).

Example 33: Preparation of 8-I|3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,21-pentaazatetracyclo| 18.2.2.111,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (compound 130) 9, - schi Zier 1 0-5 Me U o VosmM o oo (9) oder;

Z m"? ah sia -5 sia pika This is a seam

VosM

Stage 1: tert-butyl 4-I4-(5-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|isulfamoyl|-2-pyridylyamino|butyl| -2,2-dimethyl-pyrrolidine-1-carboxylate 8 0-5 7 Me 0-5 Me M Mn Si

VocmM 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (356.3 mg, 0.9846 mmol) and carbonyl diimidazole (159.7 mg, 0, 9846 mmol) were combined in tetrahydrofuran (5 ml) and stirred at room temperature for 16 h. Then, tert-butyl-2,2-dimethyl-4-14-K5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (350 mg, 0.8205 mmol) and 1,8 diazabicyclo(/5.4 .Oundec-7-ene (187.4 mg, 184.1 μL, 1.231 mmol) and the reaction mixture was stirred at room temperature for 6 hours.The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and then with brine.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient from 100 96 dichloromethane to 2095 methanol in dichloromethane to obtain tert-butyl-4-(4-((5-(Ce2-chloro- 6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|!sulfamoyl|-2-pyridyl|amino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (423 mg, 67 95) as a white solid. 1H NMR (400

MHz, Spiogotogit-a) b 8.70 (5, 1H), 8.27 (a, U - 2.9 Hz, 1H), 8.19 (a, U - 8.5 Hz, 1H), 8.08 (a, y - 8.9

Hu, 1H), 7.70 (a, U - 8.5 Hu, 1H), 6.41 (a, 9 - 8.9 Hz, 1H), 5.95 (y, U - 2.9 Hu, 1H), 5.48 (Bg5, 1H), 4.41 ( I, U - 6.8 Hz, 2H), 3.64 (a, y - 40.0, 9.2 Gu, 1H), 3.34 (5, 2H), 2.85 (d, U - 11.1 Hz, 1H), 2.06 (y, 9 - 14.5 Gu, 1H), 1.96 (d, y - 6.8 Hz, 2H), 1.86 (i, U - 9.4 Hz, 1H), 1.63 (5, 2H), 1.44 (a, 9 - 6.4 Hz, TON), 1.36 ( a, 9U - 5.68 Hz, 7H), 1.27 (a, U - 18.6 Hz, ZN), 0.65 (ID, U - 8.3, 5.0, 4.1 Hz, 2H), 0.51 - 0.36 (t,

AN), 0.35 - 0.26 (t, 1H), 0.24 - 0.14 (t, 2H), 0.13 - 0.04 (t, 2H). MO-IER t/2 calc. 769.3388, found 770.45 (M--1)x; Holding time: 0.91 min. (Method of RH A).

Stage 2: 8-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,21-pentaazatetracyclo|18.2.2.111 ,14.05,10|pentacose-1(22),5,7,9,20,23-hexane-2,2,4- trione (compound 130) и Z o oo xx 7 Ex -Z

I me shi I edei

Sy

Solution tert-butyl 4-I4-(5-C2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|isosulfamoyl|-2-pyridylyamino|butyl|-2 ,2-dimethyl-pyrrolidine-i-carboxylate (415 mg, 0.5387 mmol) in dichloromethane (2 ml) and trifluoroacetic acid (614.2 mg, 412.2 μl, 5.387 mmol) were stirred at room temperature for 4 h. Then the solvents were evaporated.

The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution and

The solvent was evaporated to give a residue which was dissolved in dimethylsulfoxide (5 ml).

Molecular sieves Z A were added and the mixture was stirred for 10 min. Cesium fluoride (245.5 mg, 1.616 mmol) and potassium carbonate (223.3 mg, 1.616 mmol) were then added, and the reaction mixture was heated at 160 °C for 24 hours. The reaction mixture was filtered through a disc filter

UMpaytap (Rigadies 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient run from 50-90 90 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain 8-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10| pentacose-1(22),5,7,9,20,23-hexane-2,2,4-trione (Compound 130) (52 mg, 15965) as a white solid. TIA NMR (400 MHz,

SNiogoiogt-a) b 8.65 (5, 1H), 8.18 (y, 9 - 2.68 Hz, 1H), 7.76 (a, U - 8.4 Hz, 1H), 7.01 (a, 9 - 8.3 Gu, 1H), 6.52 ( a, 9U - 9.1 Gu, 1H), 5.89 (y, U - 2.8 Hz, 1H), 5.24 (5, 1H), 4.41 (I, U - 6.8 Hz, 2H), 3.36 (5, 1H), 2.69 ( 5, 1H), 2.23 (5, 1H), 2.06 (Brg5, 1H), 1.97 (d, U - 6.8 Hz, 2H), 1.78 - 1.71 (t, ЗН), 1.66 (horn, 1H), 1.63 (riv .

Hz, 2H), 0.50 - 0.38 (t, 4H), 0.32 (aa, U - 9.0, 6.9 Hz, 1H), 0.23 - 0.17 (t, 2H), 0.11 (t, 2H). MS-IER t/72 calc. 633.30975, found 634.22 (Ma-1)k; Holding time: 1.66 min. (Method of RH B).

Example 34: Preparation of 8-I|3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo| 18.3.1.05,10.011,15)hetracose-1(23),5(10),6,8,20 (24),21-hexane-2,2,4-trione (Compound 131) )

Ov r i son NM

M | r Maiu Zeer 1 0th M My h o -

MN

M o o,,5 o o,, 7/5 /in. pli U vir» ZHAN o-4 MTMO s or Ma

Ka o mno 733337 Ko -KM dn on

Stage 1: tert-butyl 5-I3-(6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl| -2,2-dimethyl-pyrrolidine-1-carboxylate (c)

M. 2 and MTM to 9-5 moe and M o MH shko o MH u ru for (o) 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (300 mg, 0.8291 mmol) and di(imidazole-II-ilumethanone (117.9 mg, 0.7272 mmol) were combined in tetrahydrofuran (2.5 mL) and stirred at room temperature for 16 h. Then tert-butyl- 2,2-dimethyl-5-(3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate) (250.0 mg, 0.6060 mmol) and 1,8-diazabicyclo|5.4. Fundec-7-ene (138.4 mg, 136.0 μl, 0.9090 mmol) and the reaction mixture were stirred at room temperature for 4 hours.

The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and then with saline. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gradient from 100 95 dichloromethane to 20 95 methanol in dichloromethane to give tert-butyl 5-I3-(6-C2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazole- 1-yl|Ipyridine-

C-Carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (356 mg, 78 95) as a white solid. MO-IER t/: calc. 755.3232, found 756.5 (M) k;

Holding time: 0.63 min. (Method of RH A).

Stage 2: 8-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05 ,10.011,15)hetracose-1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (Compound 131)

O o,, iv) o. re) xx m "t

In and | de nak et "x

M - 5205» 0-7 0-7 so Z va KM le va o Mn ko

Solution of tert-butyl 5-I3-C(6-C2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|isosulfamoyl|-2-pyridylyamino|Ipropyl|- 2,2-dimethyl-pyrrolidine-y-carboxylate (356 mg,

0.4707 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (536.7 mg, 360.2 μL, 4.707 mmol) were stirred at room temperature for 4 h. Then the solvents were evaporated.

The residue was dissolved in ethyl acetate, washed with 2 ml of saturated aqueous sodium bicarbonate solution, the solvent was evaporated and dried under high vacuum. The resulting residue was dissolved in dimethylsulfoxide (5 ml), molecular sieves Z A were added, and the reaction mixture was stirred for 10 min. Cesium fluoride (214.5 mg, 1.412 mmol) and potassium carbonate (195.1 mg, 1.412 mmol) were then added, and the reaction mixture was heated at 150 °C overnight. and the filtrate was purified by the method

Reversed-phase HPLC-MS using a double gradient run of 50-90 95 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase

B -acetonitrile) to obtain /8-I3-(3,33-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,19,24-pentaazatetracycloi| 18.3.1.05,10.011,15|hetracose-1(23),5(10),6,8,20(24), 21-hexane-2,2,4-trione (Compound 131) (115 mg, 39 95 ) in the form of a white solid. 1H NMR (400 MHz, Spiogotogt-a) b (5, 1H), 8.47 (y, U - 8.6 Hu, 1H), 8.26 - 8.06 (t, 1H), 7.66 (y, 9 - 15.1 Hu, 1), 7.51 - 7.40 (t, 2H), 6.45 (0, U - 7.8 Hz, 1H), 5.95 (a, U - 2.68 Hu, 1H), 4.82 (5, 1H), 4.43 (1, 7 - 6.8 Hu, 2H ), 4.16 (a, U - 72.4 Hu, 1H), 3.34 (5, 1H), 3.09 (5, 1H), 2.38 (y, U - 68.4

Hz, 2H), 1.97 (d, U - 6.68 Hz, 2H), 1.65 (y, U - 42.4 Hz, 8H), 1.15 (5, 2H), 0.95 (5, 1H), 0.66 (di, y - 8.3 , 5.0 Hz, 2H), 0.53 - 0.37 (t, 4H), 0.32 (H, U - 9.0, 6.8 Hz, 1H), 0.23 - 0.16 (t, 2H), 0.09 (ai, U - 9.0, 4.9, 3.4 Hz, 2H). MO-IER t/: calc. 619.29407, found 620.17 (M.'-1)k; Holding time: 1.61 min. (Method of RH B).

Example 35: Preparation of 12,12,19-trimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,19,21-pentaazatetracycloi|18.2.2.111,14.05,101|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 132) in" Zier 1 ni chu Zier 2

Vosm - y '«utt-Af- - Vosm M tm? y Shivilin du i) o oo

NM and -5

IF with M so ber M. uva fe and Vira a an zi

EzS zo

M. | - and Fe and Zer 5 sya CHO 0-5 M sa MM o Hm m M m M in koi Kk a waters "NS Ezs

Stage 1: tert-butyl 2,2-dimethyl-4-(4-"methylamino)butyl|pyrrolidine-1-carboxylate and

NM to me

To a 50 mL round-bottom flask charged with tert-butyl-4-(4-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (850 mg, 3.143 mmol) in dichloromethane (15 mL) was added acetic anhydride (400 μL, 4.239 mmol) followed by triethylamine (1000 μL, 7.175 mmol).

The vessel was closed and the reaction mixture was stirred at room temperature for 45 min.

The reaction was quenched with saturated aqueous sodium carbonate (10 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate (2 x - 10 ml), dried over sodium sulfate, filtered and concentrated by mass, obtaining a clear oil, which was loaded into a 100 ml round-bottom flask and M,M-dimethylformamide (15 ml), and then sodium hydride (200 mg 60 95 mabs./wt., 5,000 mmol) and the reaction mixture was stirred for 30 min at room temperature. Iodomethane (800 μl, 12.85 mmol) was added, the vessel was closed and the reaction mixture was stirred at 50 "C for 48 hours. After cooling to room temperature, the reaction was quenched with water (-15 ml).

The crude mixture was extracted with dichloromethane (3 x 25 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by column chromatography on silica gel (gradient 0-30 95 ethyl acetate in hexane) to give a yellow oil, which was charged to a 100 mL round-bottom flask and methanol (30 mL) and potassium hydroxide (1.5 g, 26, 74 mmol). The flask was equipped with a reflux condenser, and the reaction mixture was stirred at 80 "C for 96 hours. After cooling to room temperature, the solvent was removed by mass, and the residue was dissolved in ethyl acetate (-70 mL) and water (-30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 20 mL).The combined organic extracts were washed with water (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated by mass to afford crude tert-butyl-2,2-dimethyl-4- (D-(methylamino)butyl|pyrrolidine-1-carboxylate (873 mg, 98 95) as an orange/yellow oil which was used without further purification. MO-IER t/2 calcd. 284.24637, found 285.2 ( M-AT)k; Retention time: 1.19 min. (Method RH B).

Stage 2: tert-butyl 2,2-dimethyl-4-(4-Imethyl(5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate

Zuo m, ni - 5 s i --- - - -- ana

Nam SU Vosm

In a 20 ml vial filled with tert-butyl-2,2-dimethyl-4-|4-(methylamino)butyl|pyrrolidine-1-carboxylate (350 mg, 1.230 mmol), b-chloropyridine-3-sulfonamide was added (249 mg, 1.293 mmol), potassium carbonate (250 mg, 1.809 mmol) and dimethyl sulfoxide (4 mL). The free space above the product was purged with nitrogen, the test tube was closed, and the reaction mixture was stirred at 120 "C for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (40 ml). The crude mixture was washed with water (10 ml) and saline (5 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated to wt. -4-I(4-(methyl(5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate) (143 mg, 26 95) in the form of an off-white solid. MO-IER t/7 calc. 440.24573, found 441.2 (M.-1)xh Retention time: 1.6 min (Method RH B).

Stage 3: tert-butyl 4-I4-(5-(C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|methyl-amino|butyl|-2,2-dimethyl-pyrrolidine-1- carboxylate o o o o o o o o zone" and mit"

M. ry prya sh r r ra o-4 MTMO MM s ped M ks ny i i on: ie

Coo)

In a 20 ml vial filled with 2-chloro-6-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (136 mg, 0.3620 mmol ) was added to carbonyldiimidazole (59 mg, 0.3639 mmol) and tetrahydrofuran (2 mL). The vessel was closed and the reaction mixture was stirred at room temperature for 2 h. At this point, tert-butyl-2,2-dimethyl-4-N4- Imethyl(5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (143 mg, 0.3246 mmol) in tetrahydrofuran (2 mL), followed by 1,8-diazabicyclo[5.4]fundec-7-ene (75 μL, 0.5015 mmol).The reaction mixture was stirred at room temperature for 18 h. The reaction was then quenched with water (--4 mL) and 1 M aqueous citric acid (-4 mL), and the crude mixture was extracted with ethyl acetate (3 x 10 ml).

The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient 0 90-10095 ethyl acetate in hexane) to obtain //tert-butyl-4-I4-C(5-Ce-chloro-6-I(3-(2-1P1- ( trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridyl|methylamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (167 mg, 6495) in the form of off-white solid substance. MO-IER pt/" calcd. 797.2949, found 798.4 (Ma1)g; Retention time: 2.35 min. (Method RH B).

Stage 4: 2-chloro-M-I(6-(4-(5,5-dimethylpyrrolidin-3-yl)/butyl-methyl-amino|-3- pyridyl|sulfonyl|-6-(3-(2- (11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (dihydrochloride salt) o o o DZ

M. g r ra 1, M. r r ra o--42 MOM S Mom 0-42 MOM MM

Ua Ushshch: ev

From Z "noi

In a bottle with a volume of 20 ml, filled with tert-butyl-4-(4-C(5-Ce-chloro-6-I(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl) CH2CI2 (5 mL) and hydrochloric acid (1 mL 4 .0 M, 4.000 mmol) in dioxane. The vessel was sealed and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give crude /2-chloro-M-I(6-(4-(5.5 - dimethylpyrrolidin-3-yl)/butylmethylamino|-3-pyridyl|sulfonyl|/|-6-(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide ( dihydrochloride salt) (147 mg, 91 95) as a pale yellow solid, which was used without further purification. MO-IER t/72 calcd. 697.2425, found 698.4 (Mya-1)-4; Retention time : 1.69 min (Method RH B).

Stage 5: 12,12,19-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 19,21-pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 132) b 9.6 ooo 9-7 My mk mini about. me 7 pt 9) F nyu roya "Nei Z

In a bottle with a volume of 20 ml, filled with /2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-3-yl)/butylmethylamino|-3-pyridyl|sulfonyl|/|-6-( 3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (147 mg, 0.2105 mmol) was added with potassium carbonate (152 mg, 1.100 mmol), C5E (96 mg, 0.6320 mmol) and dimethyl sulfoxide (5 mL). The free space above the product was purged with nitrogen, the tube was closed, and the reaction mixture was stirred at 150 "C for 18 hours. After cooling to room temperature, the solids were filtered with ethyl acetate eluent, the crude mixture diluted with ethyl acetate (-35 ml), washed with 1.0 M aqueous citric acid (2 x 5 ml), saline solution (5 ml), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica, gradient from 095 to 595 methanol in dichloromethane) gave

Zo 12,12,19-trimethyl-8-(3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (dihydrochloride salt) (compound 132) (64 mg , 39 95) in the form of an off-white solid substance. 1H NMR (400 MHz, DMSO-46) b 12.19 (5, 1H), 8.18 (a, Y - 2.68 Hz, 1H), 7.81 (a, Y - 8.3 Hz, 1H), 6.90 (y, Y - 8.3 Hz . ), 2.07 (1, U 2 7.1 Hz, 4H), 1.78 - 1.68 (t, 1H), 1.52 (5, 8H), 1.39 (ai, 9U 2 51.3 Hz, 2H), 1.27 - 1.05 (t, 2H) , 1.04 - 0.75 (t, 6Н). MO-IER t/2 calc. 661.2658, found 662.4 (M.-1)k; Holding time: 1.84 min. (Method of RH B).

Example 36: Preparation of 12,12,18-trimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23-pentaazatetracycloi!17.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 133)

What about Faith? i" viyur2g (e; o; M

He He Yi Doo; oh oh

M and M a: Zer z o Am zm a 12 Zer4 o o chi koni M" taya, ; ky

E o y -u o o o o o o o u g y I o- oza i uva Ge

E she M Zier 5 MM m Ma

E ho- 0-4 M -- So 5-7 and AHA

IS

Stage 1: tert-butyl 2,2-dimethyl-4-3-(methylamino)propyl|pyrrolidine-1-carboxylate tv, group that - -k that H (c) (c)

YES Ho

To a 50 mL flask charged with tert-butyl-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (869 mg, 3.389 mmol) in dichloromethane (15 mL) was added acetic anhydride (527.3 mg , 487.3 μL, 5.165 mmol), then EHIZM (884.8 mg, 1.219 mL, 8.744 mmol). The vessel was closed and the reaction mixture was stirred at room temperature for 45 minutes, then quenched with saturated aqueous sodium carbonate (-10 ml) and extracted with dichloromethane (3 x - 15 ml).

The combined organic extracts were washed with saturated aqueous sodium carbonate (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated to n.p. mass to give the crude acetate, which was combined with M,M-dimethylformamide (15 mL), with with subsequent addition of Man (225 mg 60 95 wt., 5.626 mmol) and the reaction mixture was stirred for 30 ml at room temperature. Iodomethane (1000 μl, 16.06 mmol) was added, the vessel was closed and the reaction mixture was stirred at 50 "C for 48 hours. After cooling to room temperature, the reaction was quenched with water (-- 15 ml) and the crude mixture was extracted with dichloromethane (3 x 25 ml ).

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 0 95 to 30 95 ethyl acetate in hexane) gave the methylated acetate intermediate, to which methanol (30 mL) and KOH (1.5 g, 26.74 mmol) were added.

The flask was equipped with a reflux condenser and the reaction mixture was stirred at 80°C for 96 h. After cooling to room temperature, the solvent was removed by mass, and the residue was dissolved in ethyl acetate (7 70 mL) and water (7 30 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated by massio to give tert-butyl-2,2-dimethyl-4-13- (methylamino)propyl|pyrrolidine-1-carboxylate (889 mg, 97 95) as an orange/yellow oil which was used without further purification MO-IER t/: calcd 270.23074, found 271.2 (M.- 1)xh Retention time: 1.1 min (Method RH B).

Stage 2: tert-butyl 2,2-dimethyl-4-3-(methyl(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate oo / he s

I have a 7-year-old girl, M. 2

YES

And also i) c)

b-Fluoropyridine-2 sulfonamide ( 103 mg, 0.5847 mmol) followed by diisopropylethylamine (500 μL, 2.871 mmol). The flask was closed with a membrane and heated at 90 C in a nitrogen atmosphere in an oil bath for 14 hours.

The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel (80-gram column) using a gradient system from 100 95 hexanes to 100 95 ethyl acetate to obtain tert-butyl 2,2-dimethyl-4 IZ -(methyl(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (141 mg, 58 95) as a white solid. 1TH NMR (400 MHz, DMSO-ab) b 7.65 (aa, U - 8.6, 7.2 Hz, 1H), 7.12 (5, 2H), 7.01 (a, 9 - 7.2 Hz, 1H), 6.78 (9.9 - 8.7 Hz, 1H), 3.53 (d, U - 7.8, 7.4 Hz ) 12.8, 5.7 Hz, 1H), 1.53 (ai, U - 14.6, 7.4 Hz, 2H), 1.36 (ad, U - 15.0, 10.6 Hz, 14H), 1.23 (5, ZN). MO-IER tp/2 calculation 426.23007, found 427.3 (Ma) k, retention time: 0.47 min (RH Method A).

Stage 3: tert-butyl 4-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|methyl-amino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Fe o or

Has s On mm m si Ma m 0-47 m СО0-- in ovi M 5 5-7 a i 9 ot 357

In a 20 ml scintillation vial 2-chloro-6-I3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (264 mg, 0.7026 mmol) and carbonyl diimidazole (114 mg, 0.7031 mmol) were combined in tetrahydrofuran (2.2 mL) and stirred for 120 min at 50 "C without a lid. Then tert-butyl-2,2-dimethyl-4-3-dimethyl- b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (130 mg, 0.3048 mmol) in tetrahydrofuran (3 mL) and then 1,8-diazabicyclo/5.4.O)undec-7-ene (92.80 mg, 91.16 μL, 0.096 mmol). The reaction was heated at 50 C for 16 h. The reaction was diluted with ethyl acetate (25 mL) and washed with saturated aqueous ammonium chloride (25 mL) and then with brine (25 mL ).The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The crude material was then purified by silica gel chromatography,

Zo using a shallow gradient from 10095 dichloromethane to 2095 methanol in dichloromethane. The product (still contaminated with 795 5M) was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (2 x 50 ml), dried over sodium sulfate, filtered and concentrated to give // tert-butyl-4-I3-( 6-C2-chloro-6-I(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridyl|methyl-amino|propyl| -2,2-dimethylpyrrolidine-1-carboxylate (141 mg, 55 95, purity 93 Ob) in the form of a light yellow solid. IN NMR (400 MHz, DMSOSO-ab) b 8.40 (d, 9 - 4.2, 3.6 Hz . t, 1H), 4.35 (y, U - 7.0 Hz, 2H), 3.49 (yes, U - 32.6, 9.1 Hz, ЗН), 3.03 (5, ЗН), 2.71 (I, у - 10.5 Hz, 1Н), 2.10 (d, U - 7.3 Gu, ZN), 2.00 (5, 2H), 1.85 - 1.66 (t, 1H), 1.50 (d, U - 7.7 Hz, 1H), 1.43 - 1.31 (t, 9H), 1.27 (I, U 2 10.5 Hz, 4H), 1.05 - 0.82 (t, 5H). MO-IER t/: calculated 783.27924, found 784.42 (MA) k; Retention time: 2.52 min. ( Method РХ B).

Stage 4: 2-chloro-M-((6-(3-(5,5-dimethylpyrrolidin-3-yl)upropyl-methyl-amino)-2- pyridyl|sulfonyl|-6-(3-(2-( 11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide) is known; 72

M. i, - » 0-45 IOM s shchi M" sei Her shchi -7 Her.

Oh, you know

To the solution tert-butyl 4-I3-C(6-C2-chloro-6-I(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridyl|methyl-amino|propyl)|-2,2-dimethyl-pyrrolidine-1-

carboxylate (141 mg, 0.168 mmol, 93595 purity) in dichloromethane (2 mL) was added trifluoroacetic acid (1.390 g, 939.2 μL, 12.19 mmol). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated to dryness. The crude product was treated with saturated sodium bicarbonate and then extracted with dichloromethane.

The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. |sulfonyl|-6-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide) (100 mg, 4895). MO-IER t/2 cal. 683, 2268, found 684.32 (Ma1) g Retention time: 1.72 min (Method RH B).

Stage 5: 12,12,18-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 133) o o o mon a M SS p» sia o- m - o-u s is NO mm I--7 gene 29- -- АХА nm

IS

A mixture of 2-chloro-M-I((6-I(3-(5,5-dimethylpyrrolidin-Z-yl)/upropyl-methyl-amino|-2-pyridyl|sulfonyl|- 15. 6-IZ--2 -P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (83 mg, 0.1213 mmol), potassium carbonate (100 mg, 0.7236 mmol), cesium fluoride (22 mg, 0 , 1448 mmol) and a small amount of molecular sieves Z A in dimethyl sulfoxide (4 ml) were sealed and heated to 165 C for 4 h. Then the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried ( sodium sulfate), filtered and concentrated to an orange oil, which was purified by chromatography on silica gel with a small gradient from 100 95 dichloromethane to 20 95 methanol in dichloromethane to obtain 12,12,18-trimethyl-8-(3-(2-/1- "trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracycloi!17.3.1.111,14.05,10|tetracose-1(23),5( 10),6,8,19,21-hexane-2,2,4-trione (compound 133) (32.9 mg, 42 95) in the form of bi tallow of a solid substance. 1TH NMR (400 MHz, DMSO-ab) 6 8.22 (a, 9 - 2.8 Hz, 1H), 7.78 (aa, U - 12.5, 8.0 Hz, 2H), 7.19 (9, 9 - 7.3 Hz, 1H), 6.91 (I, U - 8.2 Hu, 2H), 6.12 (y, U - 2.7 Hu, 1H), 4.52 (5,1H), 4.32, - 7.0

Hu, 2H), 3.14 (t, 1H), 2.92 (t, 4H), 2.70 (a, U - 17.7 Hu, 1H), 2.08 (t, U - 7.1 Hz, ZN), 1.94 - 1.75 (t, 1H ), 1.61 (5, ЗН), 1.49 (t, U - 13.1 Hz, 5Н), 1.34 (t, 1Н), 1.15 - 0.77 (t, 5Н). MO-IER t/2 calc. 647.2502, found 648.1 (MAT) k; Holding time: 2.29 min. (Method of RH B).

From Example 37: Preparation of 8-I|3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo |18.3.1.05,10.011,15Igtetracose-1(23),5(10),6,8,20(24),21- hexane-2,2,4-trione (enantiomer 1) (Compound 136) and 8- (3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,19,24-pentaazatetracycloY18.3.1.05,10.011,15 )tetracose-1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 137) o o. o o o o /8 re re s g to UM sa UM s still MN m- -KM le m -KM le z5 y y epapioteg 1 y epapioteg 2

Stage 1: 8-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05 ,10.011,15)hetracose-1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 136) and 8-I3- (3,3Z-dicyclopropylpropoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl-2A6-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)gtetracose- 1(23),5(10),6,8,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 137) 2

Racemic 8-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011 ,15)hetracose-1(23),5(10), 6,8,29(24),21-hexane-2,2,4--rione (115 mg) was subjected to chiral separation using NKR chromatography using Rpepotepeh SYH-4 (250 X 21.2 mm), particle size 5 μm, with a mobile phase of 60 95 methanol, 40 95 carbon dioxide at 70 ml/min for 8.0 min (injection volume - 500 μl -- 30 mg/ml in a mixture of methanol: acetonitrile: dimethyl sulfoxide (40:40:20)) with obtaining as the first eluted enantiomer 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|- 12, 12-dimethyl-2A6-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)htetracosa- 1(23),5(10), 6,68,20(24),21 -hexaene-2,2,4-trione (enantiomer 1) (Compound 136) (34.1 mg, 29 90) as a white solid; 1H NMR (400 MHz, Spiogoitogit-4) b 14.55 (5, 1H), 8.47 (y, U - 8.6

Hu, 1H), 8.16 (a, U - 33.0 Hu, 1H), 7.68 (5, 1H), 7.53 - 7.39 (t, 2H), 6.45 (j, y - 7.9 Hz, 1H), 5.96 (a, U - 2.8 Hu, 1H), 4.77 (5, 1H), 4.44 (I, 9 - 6.8 Hz, 2H), 4.16 (a, U - 64.7 Hu, 1H), 3.36 (5, 1H), 3.20 - 2.90 (t , 1H), 2.38 (a, U - 8.1 Hz, 2H), 1.97 (a, U - 6.8 Hz, ЗН), 1.72 (5, 1H), 1.57 (Brg 5, 4H), 1.36 - 1.02 (t,

ZN), 1.01 - 0.82 (t, 2H), 0.66 (aa, U - 13.4, 8.68, 4.2 Hz, 2H), 0.52 - 0.38 (t, AN), 0.37 - 0.29 (t, 1H), 0.23 - 0.16 ( t, 2H), 0.10 (ai, U - 9.4, 4.5 Hz, 2H), MO-IER t/ cal. 619.29407, found 620.17 (Ma1)x; Retention time: 1.82 min. -3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5(10),6,68,20(24),21-hexane-2,2, 4-trione (enantiomer 2) (compound 137) (24.5 mg, 17 95) as a white solid; 1H NMR (4600 MHz, chloroform-a) b 14.55 (5, 1H), 8.47 (a, U - 8.6 Hz, 1H), 8.16 (y, 9U - 32.4 Hz, 1H), 7.68 (5, 1H), 7.52 - 7.40 (t, 2H), 6.45 (a, U - 8.0 Hz, 1H), 5.96 (j, U - 2.68 Hz, 1H), 4.77 (5, 1H), 4.44 (I, U - 6.68

Hu, 2H), 4.16 (y, U - 70.4 Hz, 1H), 3.49 (5, 1H), 3.03 (a, U - 51.3 Hu, 1H), 1.97 (d, U - 6.68 Hz, 2H), 1.72 ( 5, 2H), 1.56 (5, 4H), 1.27 (y, U - 15.3 Hz, 5H), 1.02 - 0.85 (t, 2H), 0.66 (ach, y - 13.4, 8.6, 4.2 Hz, 2H), 0.51 - 0.38 (t, 4H), 0.36 - 0.27 (t, 1H), 0.25 - 0.15 (t, 2H), 0.15 - 0.05 (t, 2H), MO-IER t/7 calc. 619.29407, found 620.17 (M--1) k; Holding time: 1.82 min. (Method of RH B).

Example 38: Preparation of (145)-8-I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 145) and (145 )-8-I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111 ,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 146) b oo o khy ZM He

МН со M ери ня (о ММ -4

MN about to about to

With Z

M M M Mo x M M M mo

MN MN aiaz (isegeoteg 1 agaziegeoteg 2

Stage 1: (145)-8-I(3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 145) and ( 145)-8-I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|I-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111 ,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 146)

ooo

Gu

Ian CSR

Mn, sim cm A p-"litt

MN ooo ooo

Ku u she she

MM cm M x MM cm M

МН МН аиаз(егеотег 1 аиазииегеотег 2

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (148 mg, 0.3181 mmol), 3-(4,4-dimethylpentyl)pyrrolidin-2-one (86 mg, 0.4692 mmol), Rag(ara)Z (92 mg, 0.1005 mmol), xanthophos (58 mg, 0.1002 mmol), cesium carbonate (623 mg, 1.912 mmol) and anhydrous dioxane (3 mL) . The mixture was purged with nitrogen for 2 min, stoppered and stirred at 120 C for 21 h. After cooling to room temperature, the solids were filtered and washed with ethyl acetate, and the resulting filtrate was concentrated in vacuo.

The crude reaction mixture was purified by chromatography on a column with silica gel (0 90-5 Fo of methanol in a gradient of dichloromethane) to obtain 54 mg of the product in the form of a mixture of diastereomers, a solid substance of an off-white color. The mixture of diastereomers was purified by chiral NRC using SpigaISe! 0ОН (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 18 95 acetonitrile/methanol (90:10; no modifier)/82 95 carbon dioxide at 10 mL/min for 10.0 min (volume injection - 70 μl of a solution of 24 mg/ml in methanol:dimethylsulfoxide (90:10)) with obtaining as the first eluted diastereomer (145)-8-I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl| -12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23) ,20-hexane-2,2,4-trione (diastereomer 1) (compound 145) (19 mg, 10 95); IN NMR (400 MHz, DMSO-ab) b 12.38 (5, 1H), 7.67 (a, 9 - 8.4 Hz, 1H), 7.57 (I, 9 - 7.8 Hz, 1), 7.52 (y, 9 - 8.4 Hz . 1H), 3.91 (bgoad a, 9 - 10.7 Gu, 1H), 3.75 (d, U - 9.3, 8.7 Hz, 1H), 3.11 (Bg 5, 1H), 2.94 (Bg a, U - 13.3 Hz, 1H) , 2.82 - 2.56 (t, 2H), 2.30 - 2.17 (t, 1H), 2.10 (reg 5, 1H), 1.87 - 1.67 (t, 4H), 1.64 - 1.41 (t, 9H), 1.41 - 1.27 (t , 4H), 1.25 - 1.13 (t, 2H), 0.87 (5, 9H). MO-IER t/2 calc. 596.31445, found 597.3 (Ma1)f; Retention time: 2.32 min (LC method B), and as the second eluted diastereomer (145)-8-(3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl -2A6b-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2 ,2,4- thione (diastereomer 2) (Compound 146) 6) b 12.38 (5, 1H), 7.67 (y, 9 - 8.4 Hz, 1H), 7.57 (I, Y - 7.8 Hz, 1H), 7.52 ( a, 9U - 8.4 Hz, 1H), 7.04 (y, U - 7.2 Gu, 1H), 6.96 (ear. a, U - 8.0 Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 4.05 ( 1.9 - 9.4 Hz, 1H), 3.91 (ear, U - 10.7 Hz, 1H), 3.75 (d, y - 9.3, 8.7 Hz, 1H), 3.11 (Bg 5, 1H),

Zo 2.94 (Bg a, U - 13.3 Hz, 1H), 2.82 - 2.56 (t, 2H), 2.30 - 2.17 (t, 1H), 2.10 (horn 5, 1H), 1.87 - 1.67 (t,

AN), 1.64 - 1.41 (t, 9H), 1.41 - 1.27 (t, 4H), 1.25 - 1.13 (t, 2H), 0.87 (5, 9H). MO-IER t/ calc. 596.31445, found 597.3 (Ma-1)4; Retention time: 2.32 min (LC method B), as the second eluted diastereomer, (145)-8-I(I3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl|-12,12- dimethyl-2A6b-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexaene-2, 2,4-trione (diastereomer 2) (Compound 146) (15 mg, 8,905); 1 H NMR (400 MHz, dimethylsulfoxide-α 6 ) b 12.41 (s, 1H), 7.68 (d, U - 8.5 Hz, 1H), 7.61-7.50 (m, 2H), 7.03 (d, 9 - 7.2 Hz, 1H), 6.92 (d, U - 27.7 Hz , 1H), 6.69 (d, U - 8.5 Hz, 1H), 3.94 (t, y - 9.4 Hz, 2H), 3.82 (sq, U - 9.1 Gu, 1H ), 3.09 (s, 1H), 2.93 (d, U - 13.3 Hz, 1H), 2.68 (t, U - 10.9 Hz, 2H), 2.25 (sq, U - 8.8

Hz, 1TN), 2.08 (d, U - 8.3 Hz, 1H), 1.86-1.63 (m, 4H), 1.57 (s, 4H), 1.52 (d, 7 -4.2 Hu, 1H), 1.46 (s, ЗН), 1.41-1.08 (m, 7H) 0.86 (s, 9H); MO-IER t/2 calc. 596.31445, found 597.3 (Ma1)f; Retention time: 2.33 min (method RH B).

Example 39: Preparation of 12,12,22-trimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 . 148) and 12,12,22-trimethyl-8-(3- (2-P-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11, 18,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (enantiomer 2) ( Compound 149)

ooo ooo ooo p A nn o y o-Ktya M 8-7 more Adele 9-7 - Ag le 9-7 - Ag le

E E : E : epapioteg 1 epapioteg 2

Stage 1: 12,12,22-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 148) and 12,12,22-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11, 18,23- pentaazatetracyclol17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 2) ( Compound 149) ooo o o o o o

My" M ---zh Dembzmm I Mem m m in " Adele in Ag le in Ag le

E and epapioteg 1 and epapioteg 2

Racemic 12,12,22-trimethyl-8-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab6-thia-3,9,11,18,23 -pentaazatetracyclo!17.3.1.111,14.05,10|tetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (85 mg, 0.1299 mmol) was subjected to influence of chiral NKR chromatography.

The following NCRK protocol was used: SpigaIRak A5-3 (150 X 2.1 mm), Z μm; Mobile phase 35"C: 3095 acetonitrile:methanol (90:10), 70 90 carbon dioxide. The first eluted enantiomer was 12,12,22-trimethyl-8-(3-2-1P1-(trifluoromethyl)cyclopropyl|ethoxy)- 1 H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10)|hetracose-1(23),5(10),6,8 ,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 148 ) (34 mg, 40 95). MO-IER t/27 calcd. 647.2502, found 648.34 (M-- 1) g4; Retention time: 2.24 min. (Phase B method). The second eluted enantiomer was 12,12,22-trimethyl-8-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1 H -pyrazol-1-yl)-2A6b-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8, 19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 149 ) (35 mg, 41 95). NMR (400 MHz, DMSO-ab6) b 12.46 (5, 1H), 8.23 (y ,

In 2.8 Hz, 1), 7.83 (a, - 8.2 Hu, 1H), 7.41 (a, 9 - 8.5 Hu, 1H), 6.93 (a, U - 8.2 Hz, 1H), 6.65 (0.9 - 8.6 Hz , 2H), 6.12 (9, 9 - 2.7 Hz, 1H), 4.32 (I, U - 7.0 Hz, 2H), 4.00 - 3.79 (t, 1H), 3.27 - 3.14 (t, 1H), 2.93 (0, U - 13.2 Gu, 1H), 2.84 (I, 7 - 10.5 Hz, 1H), 2.36 (5, ЗН), 2.08 (I, U - 7.1 Hz, 2H), 1.67 (ai9, 9 - 11.6, 5.2 Hz, 1H), 1.77 (t, 1H), 1.57 (a, U - 35.9 Hz, 8H), 1.44 - 1.29 (t, 1H), 0.96 (y, U - 4.4 Hz, 2H), 0.91 (a, U - 13.2 Gu, ZN). MO-IER t/: calc. 647.2502, found 648.34 (M--1)k; retention time: 2.25 min. (Method of RH B).

Example 40: preparation of 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6bthia-1,3,9,14,22-pentaazatetracycloi|16.2.1.111,14.02 ,7| docose-2,4,6,11 (22), 12-pentane-

From 8,10,10-trione (enantiomer 1) (compound 153) and 4-13-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10Abthia-1,3 ,9,14 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11Y (22), 12-pentane-8,10,10-trione (enantiomer 2) (Compound 154) se xx Lo fo o nm your o-k Me du ziyur 1 o-0u And a! (di vivr2 in water -y-9

M SSS vier Z o le ma id; to Ge! day what o 0-0 M 30 - t de ZY de mi no t epapnotekg 1 no epapyoteg 2

Stage 1: tert-butyl 4-I3-I3-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|pyrazol-1-yl|Ipropyl| -2,2-dimethyl-pyrrolidine-1-carboxylate

(e) o o o. re) 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (521 mg, 1.440 mmol) and carbonyldiimidazole (237 mg, 1.462 mmol) were combined in tetrahydrofuran (5.0 mL) and stirred for 2 hours at room temperature. Then tert-butyl-2,2-dimethyl-4-N3-(3-sulfamoylpyrazol-1-yl)upropyl| pyrrolidine-i-carboxylate (460 mg, 1.190 mmol) followed by 1,8-diazabicyclo/5.4.O)undec-7-ene (280 μL, 1.872 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and then with saline.

The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient from 100 96 dichloromethane to 2095 methanol in dichloromethane to give tert-butyl-4-13-3-(2-chloro-6-|3-(3,3-dicyclopropylpropoxy)pyrazole-1 -yl|Ipyridine-3-carbonyl|isulfamoyl|pyrazol-1-yl|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (270 mg, 31 95) as a white solid. 1H NMR (400

MHz, Spiogotogit-a) b 9.61 (a, y - 95.1 Hz, 1H), 8.30 (y, Y - 2.9 Hz, 1H), 8.24 (I, Y - 8.9 Hz, 1H), 7.75 (a, 9 - 8.4 Hu, 1H), 7.47 (a, U - 2.6 Hu, 1H), 7.05 (a, U - 2.3 Hz, 1H), 5.97 (a, U 2 2.9 Hz, 1H), 4.43 (Y, U - 6.8 Hu, 2H), 4.20 (1, 9 - 7.1 Hz, 2H), 3.78 - 3.54 (t, 1H), 2.84 (I, U - 10.1 Gu, 1H), 2.07 (5, 1H), 1.97 (a, U - 6.8 Gu, 2H), 1.93 - 1.81 (t, 1H), 1.63 (5, 5H), 1.43 (y, U - 4.7 Hz, 9H), 1.37 - 1.23 (t, 6H), 0.72 - 0.61 (t, 2H) . 3.5 Hz, 2N). MO-IER t/2 calc. 729.30756, found 730.4 (M-a-1)k; retention time: 0.92 min. (Method of RH A).

Stage 2: 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111 ,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (c) o re; o o, o i iV i

In aa: 9-5 Metem o 0-0 M m 7 oo in odi u-m o Z s

Solution // tert-butyl-4-(3-3-(2H-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|pyrazol-1-yl) |Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (270 mg, 0.3697 mmol) in dichloromethane (1.862 mL) and trifluoroacetic acid (300 μL, 3920 mmol) was stirred at room temperature for 4 h. The solvents were then removed by i.p. masio

The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution and the solvent was evaporated. The obtained residue was dissolved in dimethylsulfoxide (5.586 ml),

Molecular sieves Z A were added to the mixture and the reaction mixture was stirred for 10 min. Cesium fluoride (171 mg, 1.126 mmol) and potassium carbonate (158 mg, 1.143 mmol) were then added, and the reaction mixture was heated at 150 C overnight. The reaction mixture was filtered through a disk filter

UMpaytap (Rigadies 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient run of 50-99° mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain racemic 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14,22-pentaazatetracycloI16 .2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (50 mg, 23 95) as a white solid. MO-IER t/2 calc. 593.27844, found 594.4 (MA) k; retention time: 2.36 min. (Method of RH B).

Stage C: 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10Abthia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02, 7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (compound 153) and 4-IZ3-(3,3-dicyclopropylpropoxy)-1 H- pyrazol-1-yl|-20,20-dimethyl-10Abthia-1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (enantiomer 2) (Compound 154)

so po De I ke DK o con -t sho odu shaeshe odu v v v epapioteg 1 v epapioteg 2

Racemic 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02 ,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (50 mg) was subjected to chiral separation by means of NKR-chromatography using a SpPigaiRak AB-N column (250 X 10 mm), Particle size 5 μm) with mobile phase 28 95 acetonitrile/methanol (90:10)/72 95 carbon dioxide at 10 ml/min for 8.0 min (injection volume - 70 μl solution - 24 mg/ml in acetonitrile/methanol/dimethylsulfoxide (82:8:10)) with obtaining as the first eluted enantiomer 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|I-20,20-dimethyl- 10A6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 153) (20 mg, 18 95); IN NMR (400 MHz, Spiogoitogt-a) b 8.63 (5, 1H), 8.17 (a, y - 2.7 Hz, 1H), 7.67 (a, Y - 8.3 Hz, 1H), 7.47 (a, 9U - 2.3 Gu , 1H), 7.07 (a, U - 2.3 Hz, 1H), 7.02 (a, U - 8.2 Hz, 1H), 5.87 (a, 9U - 2.7 Hz, 1H), 4.42 (I, - 6.8 Gu, 2H) . 2H), 2.01 - 1.94 (t, 2H), 1.81 - 1.70 (t, 1H), 1.58 (5, ЗН), 1.55 (5, ЗН), 1.47 (I, У - 12.2 Hz, 1Н), 0.87 - 0.71 (t, OH), 0.71 - 0.61 (t, 2H), 0.53 - 0.39 (t, 4H), 0.37 - 0.30 (t, 1H), 0.24 - 0.15 (t, 2H), 0.15 - 0.07 (t, 2H) , MO-IER t/: calc. 593.27844, found 594.4 (Ma1)f; Retention time: 2.39 min. 1,3, 9,14,22 pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 154 ) (23.6 mg, 47 95) as a white solid; 1N

NMR (400 MHz, chloroform-4) b 8.16 (y, 9 - 2.7 Hz, 1H), 7.65 (a, Y - 8.3 Hu, 1H), 7.46 (a, Y - 2.4 Hz, 1H), 7.06 (a, U - 2.3 Hz, 1H), 7.00 (a, U - 8.3 Hz, 1H), 5.87 (a, 7 - 2.7 Hz, 1H), 4.42 (I, U - 6.68 Hz, 2H), 4.32 (y, U - 13.5 Hz, 1H), 4.00 - 3.83 (t, 1H), 2.73 (I, U - 8.1 Gu, 1H), 2.23 - 2.09 (t, 2H), 1.97 (d, 9 - 6.9 Hz, ЗН), 1.74 ( ai, U - 11.9, 5.2 Gu, 1H), 1.58 (5, 4H), 1.54 (5, ЗН), 1.51 - 1.41 (t, 2H), 0.86 - 0.72 (t, 1H), 0.71 - 0.61 (t, 2H), 0.45 (aaaa, U - 15.6, 8.1, 4.9, 3.7 Hz, 4H), 0.38 - 0.30 (t, 1H), 0.25 - 0.18 (t, 2H), 0.12 (give, y - 11.4, 5.2, 3.7 , 3.1, 1.9 Hz, 2H). MO-IER t/2 calc. 593.27844, found 594.4 (M.-1) zhk; Retention time: 2.39 min (method RH B).

Example 41: Preparation of 12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2Ab6-thia-3,9,11 ,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 159) ii 12,12-dimethyl-8-(3 13-11- (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11,18,23 - pentaazatetracyclo!|17.3.1.111,14.05,10)tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 160)

EZS ON -vier11 o-8-o zier2 EZS. CM Vierz railway water -vy dol ---

I 4 noi EzS i vier 6 vo ton vera vod tton "o "uh willow a uh -vero (c) Y Kk i vs y he Ж vyur?7 v uv; verb v uv on i NI uva pn lower tower

Vos Vos

Vos Vos M M o o o o o o

IN; »

Vos du r SE. (c) in - she: with o and nom Go -vivr'i that Go , I se zivr 15 o77- MN Й 2 5 Mys

Ezs bor all about odo and m? и ХУ А и

Vos., s MN vody oz ooo ooo pe Te» 0-2 sho y 0-0 U zu a, S dn dy and KhR Chu / a UR es EZS EzS epapboteg 1 epapioteg 2

Stage 1: 2-P1-(trifluoromethyl)cyclopropyl|ethyl methanesulfonate o-6-o ved M- 2525 ped

A 1000 mL three-neck round-bottom flask was equipped with a mechanical stirrer, a cooling bath, a .)-Ket temperature sensor, a dropping funnel, and a nitrogen inlet/outlet. 2-(/1-(trifluoromethyl)cyclopropyl|ethanol (125 g, 811.0 mmol) and 2-methyltetrahydrofuran (625 mL) were charged into the vessel under a nitrogen atmosphere, which gave a clear, colorless solution. Stirring was started and the temperature in the vessel was recorded at 1970. The vessel was then charged with triethylamine (124.3 mL, 891.8 mmol), which was added neat in one portion. The cooling bath was then charged with crushed ice/water and the temperature in the vessel was lowered to 0 "C. The dropping funnel was charged with a solution of methanesulfonyl chloride (62.77 mL, 811.0 mmol) in 2-methyltetrahydrofuran (125 mL, 2 mL/g), which was then added dropwise over 90 minutes, resulting in the formation of a white suspension and an exothermic reaction to 1 °C. The mixtures were allowed to warm slowly to room temperature and stirring was continued at room temperature for 1 h, after which the mixture was poured into ice water (250 mL) and then transferred to a separatory funnel.The organic layer was removed and washed with 20 wt. potassium nitrate (250 ml), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel with a glass frit. The clear filtrate was concentrated under reduced pressure to give 2-[1-trifluoromethyl)cyclopropyl]ethylmethanesulfonate (185 g, 98 95) as a clear pale yellow oil. TN NMR (400 MHz, chloroform-a) b 4.36 (ddt, U - 7,1,6,4, 0.7 Hz, 2H), 3.02 (s, ЗН), 2.03 (t, In - 7.1 Hz, 2H), 1.11-0.98 (m, 2H), 0.81-0.66 (m, 2H).

Stage 2: 3-P1-(trifluoromethyl)cyclopropyl|propane nitrile o-b-o ped 06066220 ved

A 1000 mL three-neck round-bottom flask was equipped with a mechanical stirrer, a heating hood, a .)-Ket temperature sensor/controller, a water-cooled reflux condenser, and a nitrogen inlet/outlet. 2-(|1-trifluoromethyl)cyclopropylethylmethanesulfonate (50 g, 215.3 mmol) and dimethyl sulfoxide (250 mL) were charged to the vessel under nitrogen atmosphere, which gave a clear pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 19 C. Sodium cyanide (13.19 g, 269.1 mmol), added as a solid in one portion, was loaded into the vessel. The mixture was heated to a temperature of 70 "C and the conditions were maintained for 24 hours. Upon heating, all the sodium cyanide dissolved and the reaction mixture turned into a light amber suspension. After cooling to room temperature, the reaction mixture was poured into water (500 mL) and then transferred into a separatory funnel and partitioned with methyl tert-butyl ether (500 mL). The organic layer was removed, and the remaining aqueous layer was extracted with methyl tert-butyl ether (3 x 250 mL). The combined organic layers were washed with water (2 x 250 ml), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel with a glass frit.

The clear filtrate was concentrated under reduced pressure to give /- 3-(1-(trifluoromethyl)cyclopropyl|propanenitrile (30 g, 85905) as a clear amber oil. IN NMR (400 MHz, chloroform-4) 5 2.55 (t , U - 7.6 Hz, 2H), 1.93 (t, U - 7.7 Hz, 2H), 1.11-1.04 (m, 2H), 0.78-0.70 (m, 2H).

Stage C: 3-/1-(trifluoromethyl)cyclopropyl|propionic acid (c)

A 1000 mL three-neck round-bottom flask was equipped with a mechanical stirrer, a heating hood, a 9U-Ket temperature sensor/controller, a water-cooled reflux condenser, and a nitrogen inlet/outlet. Then 3-1P1-(trifluoromethyl)cyclopropyl|Ipropanenitrile (25 g, 153.2 mmol) and ethyl alcohol (375 ml) were charged into the vessel under nitrogen atmosphere, which gave a clear amber solution. Stirring was started and the temperature in the vessel was recorded at 19 "C. Then sodium hydroxide (102.1 ml of 6 M, 612.6 mmol) was loaded into the vessel, which was added in one portion. The resulting clear amber solution was heated to a temperature of 70 "C and kept for 24 hours. After cooling to room temperature, the reaction mixture was concentrated to remove ethyl alcohol. The residual aqueous solution was diluted with water (150 mL), and then transferred to a separatory funnel and partitioned with methyl tert-butyl ether (50 mL). The aqueous layer was removed and the pH was adjusted to pH - 1 using a 6 M solution of hydrochloric acid. The obtained aqueous solution was transferred to a separatory funnel and separated with methyl tert-butyl ether (250 ml).

The organic layer was removed, and the remaining aqueous layer was extracted with methyl tert-butyl ether (2 x 150 mL). The combined organic compounds were dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The clear filtrate was concentrated under reduced pressure to give 3-(1-(trifluoromethyl)cyclopropyl|ipropanoic acid (26 g, 93 95) as a clear amber oil. IN NMR (400 MHz, chloroform-a) b 2.63-2 .50 (m, 2H), 1.96-1.84 (m, 2H), 1.03--0.95 (m, 2H), 0.66-0.58 (m, U - 1.7 Hz, 2H).

Stage 4: 3-P1-(trifluoromethyl)cyclopropyl|propan-1-ol (c)

Coo)

A three-necked 1000-mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath, a dropping funnel, a .)-Ket temperature sensor, and a nitrogen inlet/outlet. Lithium aluminum hydride granules (6.775 g, 178.5 mmol) were loaded into the vessel under a nitrogen atmosphere. Then tetrahydrofuran (250 ml) was loaded into the vessel under a nitrogen atmosphere.

Stirring was started and the temperature in the vessel was recorded at 20 7C. The mixture was allowed to stir at room temperature for 0.5 h to allow the granules to dissolve.

The temperature of the reactor of the obtained gray suspension was 24 °C. Then crushed ice/water was loaded into the cooling bath and the temperature in the container was lowered to 0 °C. A solution of 3-(/1-(trifluoromethyl)cyclopropyl|propanoic acid (25 g, 137.3 mmol) in tetrahydrofuran (75 mL, 3 mL/g) was charged to the dropping funnel, and the clear pale yellow solution was added dropwise over 1 After the addition was complete, the reservoir temperature of the resulting grayish-brown suspension was recorded at 5 °C. The mixtures were allowed to slowly warm to room temperature and continued to stir at room temperature for 24 hours.

The suspension was cooled to 0 °C using a crushed ice/water cooling bath and then quenched by the very slow addition of water (6.775 mL) dropwise, then 15 wt. 95 sodium hydroxide solution (6.775 mL) and then again water (20.32 ml). The temperature of the resulting white suspension was 5 "С. The suspension was continued to be stirred at - 5 "C for 30 min and then filtered through a Buchner funnel with a 20 mm Celite glass frit. The precipitate on the filter was washed with replacement tetrahydrofuran (2 x 150 mL) and then dried under vacuum for 15 min. The filtrate dried over sodium sulfate (250 g) and then filtered through a glass frit Buchner funnel.The filtrate was concentrated under reduced pressure to give a clear pale amber oil as the desired product, 3-(1-(trifluoromethyl)cyclopropyl|Ipropane-1 -ol (21.2 g, 92 95). IN NMR (400 MHz, chloroform-4) b 3.65 (t, U - 6.0 Gu, 2H), 1.78-1.59 (m, 4H ), 0.99-80.91 (m, 2H), 0.59 (dp, U - 4.7, 1.7 Hz, 2H).

Stage 5: tert-butyl 3-I3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate

N r Zh EzS r

M. Z. M. Zh

A three-necked 5000 mL round-bottom flask was equipped with a mechanical stirrer, a heating hood, a Z-Ket temperature sensor/controller, a dropping funnel, a water-cooled reflux condenser, and a nitrogen inlet/outlet. Tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (175 g, 950.1 mmol) and tetrahydrofuran (2100 mL) were charged to the vessel under a nitrogen atmosphere, which gave a clear pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 19 "C. Then 3-P-"("trifluoromethyl)cyclopropyl|Ipropan-1-ol (175.7 g, 1.045 mol) was loaded into the vessel in its pure form in one portion, followed by the addition of triphenylphosphine (274.1 g, 1.045 mol) as a solid in one portion.The resulting clear, pale yellow solution was then treated with diisopropyl azodicarboxylate (205.7 mL, 1.045 mol) added neat dropwise over 2 h, resulting in gradual exothermic exposure up to 40 s and obtaining a transparent light-amber solution. Then the reaction mixture was heated to a temperature of 50 "C and the conditions were maintained for 2 hours. The clear amber reaction mixture was concentrated under reduced pressure, and the resulting clear dark amber oil was suspended in toluene (1400 mL) and stirred at room temperature for 1 h, during which solid triphenylphosphine oxide precipitated.

The thick suspension was filtered through a Buchner funnel with a glass frit and the precipitate on the filter was washed with toluene (2 x 500 ml). The pure amber filtrate was concentrated under reduced pressure to give a clear pale amber oil (320 g). The material was purified by flash chromatography on a silica gel column (solid on celite), eluting with a gradient from 100 95 hexanes to 20 95 ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl-3-I3-P1-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1-carboxylate (280 g, 88 95) as a transparent pale yellow oil. 1H NMR (400 MHz, DMSO-a6) b 8.07 (a, 9 - 3.0 Hz, 1H), 6.09 (a, U - 2.9 Hz, 1H), 4.15, 9 - 6.2 Hu, 2H), 1.91 - 1.75 (t , 2H), 1.76 - 1.63 (t, 2H), 1.55 (5, 9H), 0.98 - 0.84 (t, 2H), 0.74 (a, U - 3.3, 1.9 Hz, 2H).

Stage 6: 3-IZ3-1-"trifluoromethyl)cyclopropyl|Ipropoxy|-1H-pyrazole (c)

Ro m. Zh XX c m.

A 5000 ml three-neck round-bottom flask was equipped with a mechanical stirrer, a cap for

From heating, .-Ket temperature sensor/controller, water reflux cooler, drip funnel and nitrogen inlet/outlet. Tert-butyl-3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1-carboxylate (280 g, 837.5 mmol), dichloromethane (840 ml) and methyl alcohol (840 ml) were charged into the vessel under a nitrogen atmosphere. ., which gave a clear pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 19 °C.

Hydrogen chloride in 1,4-dioxane (628 ml of 4 M, 2.512 mol) was charged into the dropping funnel, which was then added dropwise over 2 h, which led to a gradual exothermic effect up to 30 °C. The resulting transparent pale yellow solution was heated to at 45 C and maintained for 1 hour. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The remaining residue was dissolved in methyl tert-butyl ether (2.24 L), then transferred to a separatory funnel and partitioned with glacial hydroxide sodium (1.256 L 2 M, 2.512 mol). The organic layer was removed, and the residual aqueous layer was extracted with tert-butyl methyl ether (2 x 500 mL). The combined organic compounds were washed with brine (2 x 500 mL), dried over sulfate of sodium (500 g) and then filtered through a Buchner funnel with a glass frit.

The transparent pale yellow filtrate was concentrated under reduced pressure to obtain 3-I3-(H1-(trifluoromethyl)cyclopropyl|propoxy|-1H-pyrazole (190 g, 97 95) in the form of a transparent light yellow oil. MO-IER t/2 calculated 234.09799, found 235.1 (M--1)g, retention time: 1.37 min (Method RH B).

Stage 7: tert-butyl 2-chloro-6-I(3-I3-P1-("trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxylate (c) XX Ge)

EzS A is M ke - mk; M ss

A 5000 mL three-neck round-bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary protective shell, a 9U-Ket temperature sensor, a water reflux condenser, a dropping funnel, and a nitrogen inlet/outlet. 3-III-P1-(trifluoromethyl)cyclopropyl|propoxy|-1H-pyrazole (188.8 g, 8061 mmol) and 000 mM dimethylformamide (2.40 L) were charged to the vessel under a nitrogen atmosphere, which gave a clear pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 17 °C. Then tert-butyl-2,6-dichloropyridine-3-carboxylate (200 g, 806.1 mmol) was charged into the vessel, which was added as a solid in one portion. The resulting clear The pale yellow solution was then treated with potassium carbonate (144.8 g, 1.048 mol) added as a solid in one portion, followed by 1,4-diazabicyclo(|2.2.2|octane (13.56 g, 120.9 mmol ), added as a solid in one portion. The resulting pale yellow suspension was left under stirring at room temperature for 24 h. The reaction mixture was cooled to 10°C using a crushed ice/water cooling bath. Water (2, 40 l), which was added dropwise over 2 h, which led to the formation of a thick suspension and an exothermic reaction up to 15 "С. The resulting suspension was continued to be stirred at 157 for 30 min, and then filtered through a Buchner funnel with a glass frit. The precipitate on the filter prom was washed by displacement with water (3 x 500 ml), and then dried in a vacuum on a funnel

Buchner for 2 hours. The material was then allowed to air dry overnight to afford tert-butyl-2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxylate (305 g, 85 95) in the form of a white granular solid. The material was used in the next stage of synthesis without additional purification. MO-IER t/72 calculated 445.138, found 446.2 (М--1) k; Retention time: 2.54 min. (Method RH B).

Stage 8:00 2-chloro-6-I3-I3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridin-3-carboxylic acid i) (o) 3 Bo MI ss g B-otn M he

A three-necked 1000 mL round-bottom flask was equipped with a mechanical stirrer, a heating hood, a U-Cat temperature sensor/controller, a dropping funnel, a water-cooled reflux condenser, and a nitrogen inlet/outlet. IN

Tert-butyl 2-chloro-6-I3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (50 g, 112.1 mmol) and 2 -propanol (250 ml) to obtain an off-white suspension. Stirring was started and the temperature in the vessel was recorded at 19C. Hydrochloric acid (93.42 ml 6 M, 560.5 mmol) was loaded into the dropping funnel, which was added dropwise over 30 minutes, which led to an exothermic reaction up to 30 "C. The resulting suspension was then heated with a reflux condenser (tank temperature - 82702 ). Upon heating, the suspension turned into a clear pale yellow solution (temperature in the vessel at this time - 7570). After stirring under reflux for - 30 min, a solid began to precipitate. The suspension was continued to stir under reflux for an additional 30 minutes, after which water (150 mL) was added dropwise over 45 minutes. The heat was then removed and the suspension continued to stir and allowed to cool slowly to room temperature. The material was collected by vacuum filtration in a glass frit Buchner funnel and the filter cake was washed by displacement 171 water/2-propanol (250 mL), then water (2 x 250 mL), then dried under vacuum in a funnel

Buchner for 30 minutes. The material was additionally dried in a vacuum oven at 45 "C for 24 hours to obtain 2-chloro-6-I3-I3-P1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carboxylic acid (41.5 g, 95 95) in the form of a white solid. NMR (400 MHz, DMSO-ab6) b 13.59 (5, 1H), 8.50 - 8.28 (t, 2H), 7.72 (y, U - 8.4 Hz, 1H), 6.20 (y, U - 3.0 Hz, 1H), 4.23 (1.9-6.2

Gu, 2H), 1.86 (dd4, U - 10.6, 6.3 Hz, 2H), 1.78 - 1.66 (t, 2H), 0.98 - 0.87 (t, 2H), 0.76 (a, U - 4.9, 1.7

Gu, 2H).

Stage 9: tert-butyl 2,2-dimethyl-4-oxo-pyrrolidine-1-carboxylate

Vos ---" (in; (in)

Di-tert-butyl dicarbonate (22.9 g, 24.11 mL, 104.9 mmol) was added to a solution of 5,5-dimethylpyrrolidin-3-one (hydrochloride) (13.08 g, 87.42 mmol), triethylamine ( 17.71 g, 24.4 mL, 175.0 mmol) and OMAR (1.1 g, 9.004 mmol) in dichloromethane (325 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 n. hydrochloric acid (300 ml) and the aqueous layer was extracted with dichloromethane (2 x 250 ml).

The organic layers were combined, washed with 5% sodium bicarbonate (250 ml) and brine (150 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl-2,2-dimethyl-4-oxopyrrolidine- 1 carboxylate (18.5 g, 99 95) as a white solid. 1H NMR (300 MHz, SOSIZ) mp 1.33-1.66 (t, 15H), 2.51 (5, 2H), 3.85 (Bi. 5., 2H). MO-IER t/ calc. 213.27, 158.2 (MS4HB)x was detected; retention time: 1.91 min. (The method of RH

AND).

Stage 10: tert-butyl 4-hydroxy-2,2-dimethyl-pyrrolidine-1-carboxylate

Vos Vos (c) on tert-butyl-2,2-dimethyl-4-oxopyrrolidine-1-carboxylate (150 mg, 0.7033 mmol) was dissolved in dry methanol (2.5 mL) and cooled in an ice bath. Mavna (30 mg, 0.7930 mmol) was carefully added and the reaction mixture was stirred at 0 "C for 1.5 hours. The reaction mixture was diluted with water (25 mL) and 1 M aqueous hydrochloric acid (0.5 mL). The aqueous layer was extracted ethyl acetate (2 x 25 mL), and the organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated by massio to give tert-butyl-4-hydroxy-2,2-dimethylpyrrolidine-1- carboxylate (150 mg, 99 95) which was used directly in the next step MO-IER tp/2 calcd 215.15215 found 216.2 (Ma1)k retention time 0.48 min (RC Method A) .

Step 11: tert-butyl 4-(2-hydroxyethoxy)-2,2-dimethyl-pyrrolidine-1-carboxylate:

Vos

Vos M x,-3354 ov on v/h

In a 250 ml flask, tert-butyl-4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (3 g, 13.93 mmol) was dissolved in MM-dimethylformamide (15 ml) at 0 "C and carefully added hydride sodium. (1.8 g 60 95 w/w in mineral oil, 45.00 mmol). The mixture was stirred at 0 "C for 15 minutes, and then 2-bromomethoxy-tert-butyldimethylsilane (9 ml, 41.95

2 mmol) at 0 "C and the mixture was allowed to warm to room temperature. The mixture was stirred for 16 hours. Then the mixture was cooled to 0 "C, quenched with water and extracted with ether. The organic extract was washed with water, dried (sodium sulfate), filtered and concentrated by mass.

The obtained orange oil was purified by chromatography on silica gel, eluting with a gradient from 0 to 3095 ethyl acetate in hexane, to obtain an intermediate compound protected by tert-butyl(dimethyl)silyl, which was dissolved in tetrahydrofuran (20 ml), treated with a solution of TVAE in tetrahydrofuran (28 ml 1 M, 28.00 mmol) and stirred for 2 hours at room temperature. The mixture was concentrated, and the residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The resulting crude material was purified by silica gel chromatography, eluting with a gradient of 0 to 20 95 methanol in dichloromethane, to give tert-butyl 4-(2-hydroxyethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.6 g, 44 95 yield ). IN NMR (400 MHz, Spiogottt-a) b 3.97 (a, U - 4.0 Hz, 1H), 3.80 - 3.34 (t, 6H), 2.05, 9 - 6.1 Hu, 1H), 1.97 (a, U - 16.4 Hz , 2Н), 1.52 - 1.30 (t, 15Н). MO-IER t/2 calc. 259.17834, found 260.17 (M'-1) k; Holding time: 0.55 min. (Method of RH A).

Stage 12: tert-butyl 4-(2-azidoethoxy)-2,2-dimethyl-pyrrolidine-1-carboxylate

Vos Vos 5-5 no V.

To a solution of tert-butyl-4-(2-hydroxyethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.6 g, 6.169 mmol) in dichloromethane (20 ml) was added triethylamine (5.2 ml, 37.31 mmol) , and then methanesulfonyl chloride (1.4 mL, 18.09 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with ice water and dichloromethane and the resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated ip massio to give the crude mesylate, which was combined with sodium azide (1.2 g, 18.46 mmol) in M,M-dimethylformamide (10 mL), and the mixture was stirred at 50 °C for 2 h. The reaction was quenched with water and extracted with ether. The organic extract was dried over sodium sulfate, evaporated in vacuo, and the residue was purified by chromatography on silica gel, eluting with a gradient from 0 to 50 95 ethyl acetate in hexane, to obtain tert-butyl-4-(2-azidoethoxy)-2,2-dimethylpyrrolidine-th carboxylate (1.33 g, 7695). 1H NMR (400 MHz, chloroform-a) b 3.96 (d, U - 4.6 Hz, 1H), 3.69 - 3.31 (t, 6H), 2.06 - 1.91 (t, 2H), 1.53 - 1.32 (t, 15H).

Step 13: tert-butyl 4-(2-aminoethoxy)-2,2-dimethyl-pyrrolidine-1-carboxylate:

Vos Vos 5-« 73 GF)

Mz y

Palladium on carbon (500 mg 10 95 wt. /wt., 0.4698 mmol). The mixture was saturated with hydrogen gas and stirred at room temperature by blowing hydrogen through the reaction mixture for 2 hours. The mixture was filtered and evaporated in vacuo to give tert-butyl-4-(2-aminoethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.188 g, 98,905). IN NMR (400 MHz, chloroform-a) b 4.00 - 3.87 (t, 1H), 3.69 - 3.35 (t, 4H), 2.94 - 2.71 (t, 2H), 2.07 - 1.83 (t, 2H), 1.47 (d , y - 9.4, 8.4 Hz, 15N).

Stage 14: tert-butyl 2,2-dimethyl-4-(2-(b-sulfamoyl-2-pyridyl)amino|ethoxy|pyrrolidine-1-carboxylate in Ode)

Yasya Vos I vm, M nar i Z lm er y

E SAN

In a 20 mL microwave sealed vial, a solution of tert-butyl-4-(2-aminoethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.188 mg, 4.598 mmol), 6b-fluoropyridine-2-sulfonamide (810 mg, 4.598 mmol) and diisopropylethylamine (4 ml, 22.96 mmol) in n-VION (10 ml) were stirred at 150 C for 16 hours. The solvent was removed by vacuum, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, evaporated and purified by chromatography on silica gel, eluting with a gradient from 0 to 40% ethyl acetate in hexane, to obtain tert-butyl-2,2-dimethyl-4-(2-(b-sulfamoyl-2-

From pyridyl)amino|ethoxy|pyrrolidine-1-carboxylate (1.500 g, 66 95). MO-IER t/:2 calc. 414.1937, found 415.3 (M--1) k; retention time: 0.61 min. (Method of RH A).

Stage 15: tert-butyl 4-(2-((6-Ce-chloro-6-I3-19-(11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|- 2- pyridylamino|ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate оо ЕзС о to

SEZ i) in I

NM 7 xx M eh v Ma MM Me s Ma

M. - 0-7 o " s Vos MN "ie de Vos MN re "M -i "M i-i vod; -

From a 50 mL flask charged with carbonyldiimidazole (208 mg, 1.283 mmol) and 2-chloro-6-I3-I|3-

N-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (500 mgHg, 1.283 mmol) was pumped off with nitrogen and refilled with it (Х). Tetrahydrofuran (8 ml) was added and the mixture was stirred at 50 "C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-(2-((b-sulfamoyl-2-pyridyl)amino|ethoxy|pyrrolidine) was added -1-carboxylate (483 mg, 1.165 mmol) and 1,8-diazabicyclo/5.4.Oundec-7-ene (450 mg, 2.956 mmol) in tetrahydrofuran (6 mL) and the mixture was stirred overnight at 50 °C. The reaction was diluted ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated and purified by chromatography on silica gel, eluting with a gradient from 0 to 50 95 ethyl acetate in hexane, to obtain some pure fractions. The mixed fractions were purified by reverse-phase preparative HPLC (C18): 1-99 95 gradient of acetonitrile in water/hydrochloric acid modifier Pure fractions from both purifications were combined to give tert-butyl-4-(2-(6-Ce-chloro-6-

YZ-YZ-P-"trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|ethoxy|-2,2-dimethylpyrrolidine-1-carboxylate (483 mg, 53 95 ). MO-IER t/2 calc. 785.25854, found 786.33 (M--1)k; Holding time: 0.88 min. (Method of RH A).

Stage 16: 2-chloro-M-((6-(2-(5,5-dimethylpyrrolidin-3-yl)uoxyethylamino|-2-pyridyl|sulfonyl|-6-

YZ-YZ-P-"trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carboxamide

Ezs o o Ezo o o o

M. 2 M. 2 M. - Mach o-4 M M s o-4 M M s va vos mno 7 ha MN "M u-i nm t-e- --9 -9

Solution of tert-butyl-4-(2-(6-Ce-chloro-6-I3-(3-P1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|ethoxy|-2,2-dimethylpyrrolidine-1-carboxylate (483 mg, 0.61 mmol) in dioxane (5 mL) was treated with hydrochloric acid in dioxane (b mL 6 M, 36.00 mmol) and stirred at room temperature within 2 hours.

The mixture was evaporated under vacuum and the residue was quenched with aqueous sodium bicarbonate. The formed white precipitate was filtered off and washed with ethyl acetate. The aqueous phase was additionally extracted with ethyl acetate, the combined organic extracts were dried over sodium sulfate, filtered and evaporated to obtain an additional solid product, which was combined with the previously precipitated solid and dried in a vacuum to obtain 2-chloro-M-((6- (2-(5,5-dimethylpyrrolidin-3-yl)uoxyethylamino)|-2-pyridyl|sulfonyl|-6-I(3-I3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine - Z-carboxamide (350 mg, 83 95). MO-

IER t/2 calc. 685.2061, found 686.3 (M--1); retention time: 0.64 min. (Method of RH A).

Stage 17: 12,12-dimethyl-8-(3 13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2Ab-thia-3,9,11 ,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21- hexane-2,2,4-trione

EzS (o) 9uo obo x M hu and I oyu so

M. 2 M. 2 | H 5-5 M s Mecca 15 sh- MN o (in; dr o in)

Ezo

Cesium fluoride (162 mg, 1.066 mmol), potassium carbonate (367 mg, 2.655 mmol), and 4A molecular sieves (300 mg) were combined in a 5 mL microwavable vessel, and the vial was evacuated and re-injected with nitrogen . Then a solution of 2-chloro-M-|((6-(2-(5,5-

From dimethylpyrrolidin-3-yl)oxyethylamino|-2-pyridyl| sulfonyl|-6-I(3-I3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide) (360 mg, 0.5247 mmol) in dimethylsulfoxide (5 mL) and the mixture was stirred at 150 "C overnight. The mixture was filtered and purified by reverse-phase preparative HPLC (C18): a gradient of 1-99 95 acetonitrile in water/hydrochloric acid modifier (15 min) to give 12,12-dimethyl-8-(3- 13-P1-(trifluoromethyl)cyclopropyl|ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2lAl6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111,14.05, 10) htetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (118.2 mg, 34 95). NMR (400 MHz, Spiogoitogit-a) b 9.51 (5, 1H), 8.16 (a, 9U - 2.7 Hz, 1H), 7.90 (a,

U - 8.0 Hz, 1H), 7.60 (her, U - 7.68 Hz, 1H), 7.52 (a, U - 7.2 Hz, 1H), 7.15 (a, 9 - 8.2 Hz, 1H), 6.65 (j, y - 7.3 Hz, 1H), 5.90 (y, U - 2.7 Hz, 1H), 4.82 (5, 1H), 4.33 (90.9. - 7.1 Hz, 1), 424.9 - 6.1 Hz, 2H), 4.06 ( 5, 1H), 3.82 (I, U - 9.5 Hu, 1H), 3.58 (a, U - 12.1 Hu, 1H), 3.43 - 3.28 (t, 2H), 3.15 - 3.03 (t, 1H), 2.23 - 2.14 (t, 1Н), 1.95 (ad, U - 11.0, 6.3 Hz, ЗН), 1.75 (yes, У - 10.0, 6.2 Hz, 2Н), 1.64 (5, ЗН), 1.60 (5, ЗН), 0.99 - 0.95 (t, 2H), 0.60 (a, U - 4.68 Hz, 2H). MO-IER t/2 calc. 649.22943, found 650.29 (MAT) k; Holding time: 2.12 min. (Method of RH B).

Stage 18: 12,12-dimethyl-8-(3-13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2Ab-thia-3,9,11 ,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 159) and 12,12-dimethyl-8-(3-13-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11,18 ,23-

pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 160) boron and m? х 0-7

With / a DR

EZS o to o to

Mu Mi xx M oh xx M xx 0-7 0-7

I / shcha Re I / what Hr le

EzS EzS epapboteg 1 epapboteg 2

Racemic 12,12-dimethyl-8-(3 13-P1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-15-oxa-2Ab-thia-3,9,11,18,23 -pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (116 mg, 0.18 mmol) was subjected to chiral separation by the NKR chromatography method using SpigaIRak AZ-N (250 X 21.2 mm, particle size 5 μm) with a mobile phase of 28 95 acetonitrile/methanol (90:10)/72 95 carbon dioxide at 70 ml/min for 8.0 min (injection volume - 500 μl of a 32 mg/ml solution in acetonitrile/methanol (90:10)) with obtaining 12,12-dimethyl-8-(3-13-|1- (trifluoromethyl)) as the first eluted enantiomer cyclopropyl|propoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)tetracose-1(23 ),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (compound 159) (48.3 mg, 28 95); MO-IER t/2 calc. 649.22943, found 650.32 (MA1)k; Retention time: 2.12 min (LC method B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl) - 15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2, 2,4-trione (enantiomer 2) (compound 160) (56.0 mg, 48 95); IN NMR (400 MHz, DMOO-ab) 6 12.57 (5, 1H), 8.19 (a, 9 - 2.68 Hu, 1H), 7.78 (a, U - 8.1 Hu, 1H), 7.58, 9 - 7.7 Hz, 1H ), 7.09 (a, y - 7.3 Hz, 2H), 6.93 (a, 9 - 8.1 Hz, 1H), 6.70 (a, U - 8.3 Hz, 1H), 6.11 (a, 9 - 2.7 Hz, 1H), 4.19 1.9U - 6.2 Hz, 2H), 4.17 - 3.99 (t, 2H), 3.88 (I, U - 11.7 Hz, 1H), 3.60 (a, U - 12.9 Gu, 1H), 3.27 - 2.75 (t ) 5, 2H). MO-

IER t/2 calc. 649.22943, found 650.43 (M. 1); Retention time: 2.12 min (method RH B).

Example 42: Preparation of (145)-12,12-dimethyl-8-(3-(3-/1-(trifluoromethyl)cyclopropyl)propoxy)-1H-pyrazol-1-yl)-2A6-thia-3 ,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 161) о о оо оо оо se и ос с | sh ey vir 1 o-0s zm s mo vier2 to VosM VosmM.

EE GE

0 9 0 oo

Ж m Ж Ж m"? y

With NM MN -er3, with Z Ya

E E 7? on A i: E

Stage 1: tert-butyl (45)-4-3-((6-Ce-chloro-6-I3-(3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carbonyl| sulfamoyl|-2-

Zo pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

I o o to m de na- ise and 0-5 MM TO -80- o-(msmte OM

IS

GE EE

To a solution of 2-chloro-6-I3-I3-/1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (10 g, 25.6 mmol) in tetrahydrofuran (100 ml) carbonyldiimidazole (4.7 g, 27.71 mmol) was added, and the mixture was stirred at ambient temperature for 90 min. Tert-butyl (45)-2,2-dimethyl-4-I3-|(6-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-i-carboxylate (12.0 g, 29.09 mmol) in tetrahydrofuran (50 mL), followed by 1,8-diazabicyclo/5.4.F)undec-7-ene (11.5 mL, 76.90 mmol), and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water (250 mL) and the mixture was slowly acidified with aqueous hydrochloric acid (23 mL, 6 M, 138.0 mmol). The mixture was extracted with ethyl acetate (500 ml) and the organic phase was separated. The organic phase was washed with 300 ml of saline solution, dried over magnesium sulfate, filtered and concentrated by massio. The crude product was divided into 3 equal parts, acetonitrile was added and chromatographed on a 415 C18 reverse phase column, eluting with a gradient from 50 95 to 100 95 acetonitrile in water to obtain the product, tert-butyl (45)-4-I3-C6-Ce- ( 13.63 g, 68 95) in the form of a waxy solid. TN NMR (400 MHz, DMSO-ab) b 12.75 (5, 1H), 8.39 (1, U - 2.2 Hz, 1H), 8.10 (a, U - 8.4 Hz, 1H), 7.70 (a, 9 - 8.3 Hz, 1H), 7.62 (da, U - 8.5, 7.2 Hz, 1H), 7.24 - 7.14 (t, 2H), 6.74 (0, U - 8.5 Hz, 1H), 6.20 (aa, U - 68.6, 2.9 Hz, 1H), 4.23 (1.9 - 6.2 Hz, 2H), 3.51 (1, U - 18.4, 9.2 Hz, 1H), 3.24 (5, 2H), 2.74 (I, 9 - 10.5 Hu, 1H), 2.05 - 1.96 (t, 1H), 1.91 - 1.69 (t, 5H), 1.51 (a, U - 15.6, 7.1 Hz, 2H), 1.40 - 1.27 (t, 15H), 1.18 (5, ZN), 0.97 - 0.88 (t, 2H), 0.80 - 0.71 (t, 2H). MO-IER t/2 calculated 783.27924, found 784.3 (M--1) Well, time will tell time: 2.38 min. (Method of RH B).

Stage 2: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridylIisulfonyl|- 6-I3-I(3-P1-(trifluoromethyl) cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) ooo t oo y m". Ж 7 m? 7

Mom what s t -52 mm what s what 0-7 0-7 a VosM MN a NM MN

E AH E JI

RE EE "gne

To the solution tert-butyl (45)-4-3-((6-Ce-chloro-6-I3-(3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl |-2-

Hydrochloric acid in dioxane (20 ml, 4 M , 80.00 mmol). The mixture was stirred at ambient temperature for 16 h. The solvent was removed in vacuo and the residue was further evaporated from 200 mL of toluene to give 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl| sulfonyl/| -6-

13-13-P-"trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (12.7 g, 97 95), which was used without further purification. 1H NMR (400 MHz, DMSO-ab) 5 12.80 (5, 1H), 9.31 (5, 1H), 9.14 (5, 1H), 8.41 (y, U - 2.9 Hz, 1H), 8.11 (a, - 8.3 Hz, 1H), 7.72 (a, 9 - 8.3 Hz, 1H), 7.63 (aa, U - 8.5, 7.2 Hz, 1H), 7.19 - 7.15 (t, ЗН), 6.78 (ai9, y - 8.6, 0.7 Hz . - 11.6, 7.2, 5.9 Hz, 1H), 2.43 - 2.32 (t, 1H), 1.95 - 1.81 (t, ZH), 1.77 - 1.68 (t, 2H), 1.61 - 1.31 (t, 8H), 1.25 (5 , ZN), 0.96 - 0.88 (t, 2H), 0.81 - 0.70 (t, 2H). MO-IER tp/2 calc. 683.2268, found 684.3 (M--1) k; retention time: 2.47 min. (Method РХ 0).

Stage 3: (145)-12,12-dimethyl-8-(3-13-11-"trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11, 18,23-pentaazatetracyclo|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 161)

o o o o or

M. and V, Ma Mk V Mak and shvi shko and shi i

Z nm MN Z I li ; AD;

EE "noi EE

To the solution of 2-chloro-M-((6-(3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2- pyridyl|sulfonyl|-6-(3-(3-(/1 -(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (12.7 g, 16.77 mmol) in MMP (200 ml) was added potassium carbonate (11.47 g, 82 .99 mmol) followed by the addition of cesium fluoride (2.75 g, 18.10 mmol).

The mixture was purged with nitrogen for 5 min. The mixture was heated at 150 °C for 22 h. The reaction mixture was then cooled to room temperature and added to cooled water (600 mL). The mixture was carefully acidified with aqueous hydrochloric acid (26 mL, 6 M, 156.0 mmol) to give a cream-colored foamy suspension. . The suspension was stirred at ambient temperature for 1 h. The solid was collected by filtration using a Buchner funnel with a medium frit. The wet filter cake was diluted with acetonitrile and chromatographed on a C18 reverse phase column, eluting with a gradient system of 50 95-100 95 acetonitrile in water, obtaining an off-white foam, which was then dried in a vacuum at 45"С for 3 days, obtaining /(145)-12,12-dimethyl-8-(3-13-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1 N-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 161) (6.0 g, 55 95 ). IN NMR (400 MHz, DMSO-46) b 12.48 (5, 1H), 8.21 (a, U - 2.7 Hz, 1H), 7.81 (a, U-8.2Gu, 1H), 7.57 (da, y - 8.5, 7.2 Hz, 1H), 7.05 (a, 9 - 7.1 Hz, 1H), 6.97 (a, U - 8.5 Hz, 1H), 6.91 (a, - 8.2 Hz, 1H), 6.71 (a, U - 8.5 Gu, 1H), 6.12 (a, U - 2.8 Hz, 1H), 4.20 (1, 7 - 6.2 Hz, 2H), 3.92 (a, 9U - 12.5 Hz, 1H), 3.16 (5, 1H), 2.95 (9, U 2 13.3 Hu, 1H), 2.71 (Y, U 2 11.1 Hu, 1H), 2.12 (5, 1H), 1.84 (a, y - 7.8, 6.3 Hz, ЗН), 1.80 - 1.67 (t, ЗН), 1.60 (5, 6H), 1.51 (5, ЗН), 1.31 (d, y - 12.0 Hz, 1H), 0.97 - 0.87 (t, 2H), 0.76 (d, y - 3.0, 1.7 Hz, 2H). MO-IER t/: calc. 647.2502, found 648.3 (Ma) k; retention time: 9.64 min. (Method RH B).

Example 43: Preparation of 8-I|3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab-thia-3,9,11,18, 23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 162) and 8- I(3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-ylI-12,12-dimethyl-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1 .111,14.05,10)htetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 163) du ooo uv; t Go cher 1 y-u what a Go cher2 d- - Mn z cha zi o My chn r -- d- -T ooo b 9 she

M. 2 M. vivrez D- 4 Ma A. 4 M o " Le sho " LU oo " DOR v epapioteg 1 epapioteg 2

Stage 1: 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-((b-(2-(5,5- dimethylpyrrolidin-3-yl)uoxyethylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide o o, o oyu t» ni So m on, M. na M.

M. - o M' SI -- Vosm - Nm -e-

O-o water

From a 50 mL flask with 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carboxylic acid (400 mg, 1.106 mmol) and carbonyldiimidazole (270 mg, 1.665 mmol) and nitrogen (ХХ) was added again. Dry tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for 90 min at 50 "C. Then a solution of tert-butyl-2,2-dimethyl-4-(2-(6-sulfamoyl-2-pyridyl)amino|ethoxy| pyrrolidine-1-carboxylate (158 mg, 0.3812 mmol) and 1,68-diazabicyclo|5.4.Fundec-7-ene (430 mg, 2.825 mmol) in tetrahydrofuran (4 mL). The reaction was heated at 50 "C overnight The reaction was diluted with ethyl acetate and washed with water.

The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by chromatography on silica gel eluting with a gradient of 0 to 50 95 ethyl acetate in hexane to give an intermediate compound which was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (1000 µL, 12, 98 mmol) and stirred for 2 h at room temperature. The solvent was removed by mass and the residue was quenched with aqueous sodium bicarbonate and ethyl acetate. A white solid precipitate formed. The biphasic mixture was filtered and the solid product was washed with ethyl acetate.

The organic extract was separated from the aqueous extract and dried over sodium sulfate, filtered and evaporated using a massio. The solid material from the filter and the residues after evaporation were combined and dried by mass to obtain 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-((b-(2- (5 ,5-dimethylpyrrolidin-3-yl)/oxyethylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (310 mg, 43 95). MS-IER t/2 calcd. 657.25, found 658.32 (M --1)x; retention time: 0.68 min. (Method of RH

IN).

Stage 2: 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 156) o o o 9 Chu

M ro M. M. 2 Ma 0-77 oi --- z o-i 038 Yum M in MN m A LO rn

NM

Po-ia 2-chloro-6-3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-((6-(2-(5,5-dimethylpyrrolidin-3-yl)uoxyethylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (320 mg, 0.4862 mmol), potassium carbonate (340 mg, 2.460 mmol), cesium fluoride (150 mg, 0.9875 mmol), and molecular sieves Z A (300 mg) with were combined, sealed and purged with nitrogen. Dimethyl sulfoxide (4 mL) was added and the mixture was stirred at 150 °C overnight. obtaining 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo|17.3. 1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 156) (92.5 mg, 30 95). MO-IER t /:2 calculated 621.2733, found 622.31

Zo (Ma1) xx; retention time: 2.26 min. (Method of RH B).

Stage 3: 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 162) and 8-I3-( 3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10 )hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 163) OR o epapioteg 1 epapboteg 2

Racemic 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo| 1 7.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 156) (90 mg, 0.145 mmol) was subjected to chiral separation by by NKR chromatography using SpigaIRak A5-H (250 X 10 mm, particle size 5 μm) with a mobile phase of 40 95 acetonitrile/methanol (90:10)/60 95 carbon dioxide at 10 ml/min for 8.0 min ( injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10)) with obtaining as the first eluted enantiomer 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl| - 12,12-dimethyl-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19 ,21-hexane-2,2,4-trione (enantiomer 1) (compound 162) (28.4 mg, 19,965); MO-IER t/2 calc. 621.2733, found 622.38 (M--1)f; Retention time: 2.26 min. 2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4- trione (Compound 163) (enantiomer 2) (35.4 mg, 39 95); IN NMR (400

MHz, DMSO-46) b 12.58 (5, 1H), 8.19 (a, 9-2.7 Hz, 1H), 7.79 (a, U - 8.2 Gu, 1H), 7.62 - 7.55 (t, 1H), 7.11 (da , 9 - 16.4, 5.9 Hz, 2H), 6.94 (a, U - 8.2 Hz, 1H), 6.70 (a, 9 - 8.5 Hz, 1H), 6.10 (a, - 2.7 Gu, 1H), 4.36 (1, 7 - 6.8 Hz, 2H), 4.19 - 4.00 (t, 2H), 3.88 (Y, U - 11.3 Gu, 1H), 3.60 (a, U - 13.0 Hz, 1Hn), 3.22 (5, 1H), 2.86 ( a, U - 9.5 Hz, 1H), 2.07 (aa, U - 11.8, 5.9 Hz, 1H), 1.89 (d, U - 6.8 Hz, 2H), 1.78 (I, U -10.9 Hz, 1H), 1.57 ( a, U - 10.0 Hz, 6H), 0.68 (di, U - 8.4, 5.0 Hz, 2H), 0.39 (d, y - 5.9 Hz, 4H), 0.34 - 0.24 (t, 1H), 0.20 (ai, 9 - 10.4, 5.2 Hz, 2H), 0.03 (actions, U - 8.0, 4.0 Hz, 2H), MO-IER t/2 calc. 621.2733, found 622.42 (Ma-1)k; Retention time: 2.25 min (method RH B).

Example 44: Preparation of 20,20-dimethyl-4-(3-13-(/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 ,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa- 2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 165) and 20 ... 1.111,14.02,7|docose-2(7),3,5,11 (22), 12-pentane-8,10,10-trione (enantiomer 2) (Compound 166) ha I BY se zier 1 vay zzeer2 o EE E 5-0 M si EE I pr - 25 (is) r 9 to -- DE -- DE -5 M M 0-7 -- --

And I have water, and I use a knife; ; knife handle; is EE epapioteg 1 EE epapioteg 2

Stage 1: tert-butyl 4-(3-I3-(2-chloro-6-(3-I3-/1-("trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl| pyrazol-1-yl|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate ooo dl z SA Yu

What about 9-0 a -m shshch

(c) 2H-chloro-6-13-13-11-trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-ylpyridine-3-carboxylic acid (275 mg, 0.7056 mmol) and carbonyldiimidazole (130 mg, 0.8017 mmol) were combined in anhydrous tetrahydrofuran (5 ml) and stirred for 60 min at 50 "C. Then a tetrahydrofuran solution (7 ml) of tert-butyl-2,2-dimethyl -4-(3-(3-sulfamoylpyrazol-1-yl)upropyl|pyrrolidine-1-carboxylate (206 mg, 0.5330 mmol) and 1,8-diazabicyclo(|5.4.0undec-7-ene (200 μl, 1.337 mmol). The reaction was heated at 50 °C for 4 h. The reaction was diluted with ethyl acetate and washed with TM citric acid solution, and then with saline solution.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 75 95 ethyl acetate in hexane to give an off-white solid, tert-butyl-4-(3- I3-((2-chloro-6-I3-I3-1-("trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|pyrazol-1-yl|Ipropyl|-2,2 -dimethylpyrrolidine-1-carboxylate (226 mg, 56 95).

From MO-0ER t/» calc. 757.2636, found 758.32 (M--1) same; retention time: 0.88 min. (Method of RH A).

Stage 2: 20,20-dimethyl-4-(3 (13-/1-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 22- pentaazatetracycloi16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound 155)

o o o o- Mo ss m duo rya dk M U 4-7 SO

E by o- mm M

EE vl v vodo

ME

Oh k r

Tert-butyl 4-I3-I3-C2-chloro-6-I3-I3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazol-1-yl|propyl| -2,2-dimethylpyrrolidine-1-carboxylate (226 mg, 0.2981 mmol) was dissolved in dichloromethane (5 mL) and hydrochloric acid in dioxane (2 mL 4 M, 8.000 mmol) was added to the mixture and stirred at room temperature for 30 min . The mixture was concentrated to dryness under reduced pressure and the residue was combined with potassium carbonate (250 mg, 1.809 mmol), cesium fluoride (73 mg, 0.4806 mmol), 3 A molecular sieves, and dimethyl sulfoxide (b mL) in a vial purged with nitrogen. , stoppered, heated to 140°C and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by reverse phase preparative chromatography (C18 column, 3095 to 9995 acetonitrile (no modifier) in water (5mM hydrochloric acid) for 30 minutes) to give a white solid characterized as 20 ... 1.111,14.02,7|docose-2(7),3,5,11(22),12- pentane-8,10,10-trione (compound 155) (96 mg, 51 95). IN NMR (400 MHz, DMSOO-ab) b 12.69 (5, 1H), 8.18 (a, 9 - 2.8 Hz, 1H), 8.00 (a, U - 2.3 Hz, 1H), 7.71 (a, 9 - 8.1 Hz , 1H), 7.04 - 6.80 (t, 2H), 6.10 (a,

U 2.8 Gu, 1H), 4.30 - 4.05 (t, 4H), 2.07 (5, ЗН), 1.99 - 1.66 (t, 6Н), 1.55 (5, ЗН), 1.47 (5, ЗН), 1.33 (U - 12.3 Hu, 1H), 0.98 - 0.87 (t, 2H), 0.75 (5, 2H), 0.64 (5, 1H). MO-IER t/2 calc. 621.2345, found 622.24 (M.-1) k; retention time: 2.22 min. (Method of RH B).

Stage 3: 20,20-dimethyl-4-(3-13-1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 22-pentaazatetracycloi16 .2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 165) and 20,20-dimethyl -4-(3-(3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111, 14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 166) (c) oo i o dui i o du - Z M B M 5 certain souk, she eh

RE Ge epapboteg 1 shi epapioteg 2

Racemic //20,20-dimethyl-4-(3-73-(1-trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 22 -pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound 155) (88 mg, 0.1401 mmol ) were subjected to chiral NKR chromatography.

The following NKR protocol was used: SpigaIRak Az-3 (150 X 21 mm), Z μm; 35 "С. Mobile phase: 28 95 acetonitrile:methanol (90:10), 72 95 carbon dioxide with a flow rate of 0.5 ml/min.

The first eluted enantiomer was 20,20-dimethyl-4-(3-13-|1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 165) (36 mg , 82 95). MO-IER t/2 calc. 621.2345, found 622.24 (MA); Holding time: 2.21 min. (Method of RH B). The second eluted enantiomer was 20,20-dimethyl-4-(3-13-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 ,22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 166) (34 mg, 77 95). IN NMR (400 MHz, DMSOSO-ab) b 12.69 (5, 1H), 8.18 (a,

U 2.8 Hz, 1H), 8.00 (a, U - 2.3 Hz, 1H), 7.71 (a, 9 - 8.1 Gu, 1H), 7.04 - 6.80 (t, 2H), 6.10 (y, U - 2.8

Hu, 1H), 4.30 - 4.05 (t, 4H), 2.74 - 2.63 (t, 1H), 2.07 (5, ЗН), 1.99 - 1.66 (t, 7Н), 1.55 (5, ЗН), 1.47 (5, ZN), 1.33 (Her, U - 12.3 Gu, 1H), 0.98 - 0.87 (t, 2H), 0.75 (5, 2H), 0.64 (5, 1H). MO-IER t/ calc. 621.2345, found 622.35 (M.-1)x; retention time: 2.21 min. (Method of RH B).

Example 45: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23-

pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 174) and (145)-12,12-dimethyl-8-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-2A6-thia-3,9,11,18, 23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 175 ) (c) u nya s r2 p verz

SEZ SEZ MVp 0027 o Z xx M xx cm cm

Ezo Z v bor boju y z xx x -Z "xx ta rya I ta rah

MN Mn

EZS EZS diaziyegeoteg 1 aiazbegeoteg 2

Stage 1: 1-(3-bromopropyl)-1-(trifluoromethyl)cyclopropane

KO m ----ya

SEz SEz

A solution of molecular bromine (130 μl, 2.524 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of triphenylphosphine (655 mg, 2.497 mmol) in anhydrous dichloromethane (10 ml) in a nitrogen atmosphere at -15 "C for 8 min and after completion of the addition (pale yellow solution), the mixture was stirred for another 15 min at -15 "С. Then the mixture was cooled to -30 C and a solution of 3-P1-(trifluoromethyl)cyclopropyl|propan-1-ol (500 mg, 2.379 mmol) and pyridine (202 μL, 2.498 mmol) in dichloromethane (3 mL) was added dropwise over 5 minutes, and upon completion of the addition, the mixture was heated to -57C and stirred for 1 hour. Then the reaction mixture was poured into pentane (250 ml), resulting in the formation of a mass of white precipitate.

This suspension was filtered through celite and the filtrate was evaporated on a rotary evaporator (250 mbar and 30 C water bath) to give a white solid. Pentane was added to this solid, the mixture was briefly sonicated and filtered. Concentration of this filtrate gave a white solid, which was again briefly sonicated with pentane and filtered to give crude 1-(3-bromopropyl)-1-(trifluoromethyl)ucyclopropane (500 mg, 6495) as a clear oil. 1H NMR (400 MHz, chloroform-4) 5, 3.42 (t, U - 6.4 Hz, 2H), 2.09-1.95 (m, 2H), 1.71 (d, U - 5 .8 Hz, 2H), 1.36-1.20 (m, 2H), 1.02-0.93 (m, 2H), 0.61-0.58 (m, 2H). NMR showed the purity "- 70 95. The product was used in the next stage without additional purification.

Stage 2: 1-benzyl-3-I3-11-(trifluoromethyl)cyclopropyl|propyl|pyrrolidin-2-one (0) c)

Head of the Ministry of Internal Affairs of Ukraine

SEz SE"

A three-necked 100 ml flask was dried using a heat gun under vacuum and filled with nitrogen. The flask was charged with 1-benzylpyrrolidin-2-one (0.21 mL, 1.312 mmol) and

Anhydrous tetrahydrofuran (2 ml). After cooling to -78 "С, a solution of n-butyllithium (0.59 ml, 2.5 M, 1.475 mmol) (2.5 M in hexane) was added dropwise, causing the formation of a pink solution. After stirring at -78 "С for 20 min (the solution became pale yellow) a solution of /1-(3-bromopropyl)-1-(trifluoromethyl)ucyclopropane (500 mg, 1.515 mmol) in tetrahydrofuran (0.5 ml) was added dropwise (the color became dark yellow) . The mixture was stirred in a cooling bath, which was allowed to slowly warm to room temperature. After 14 h, the mixture was quenched by adding saturated aqueous ammonium chloride (50 ml). The product was extracted with ethyl acetate (2 X 30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using a gradient of ethyl acetate (0 to 100 95 over 30 min) in hexane to give 1-benzyl-3-I3-P1-(trifluoromethyl)cyclopropyl|propyl|pyrrolidin-2-one (227 mg , 53 Ob) in the form of a colorless oil. "IN NMR (400 MHz, Spiogothogite-a) b 7.37 - 7.16 (t, 5H), 4.49 (a, U - 14.7

Hu, 1H), 4.41 (y, 7 - 14.7 Hu, 1H), 3.22 - 3.14 (t, 2H), 2.45 (da, U - 8.9, 4.3 Hz, 1H), 2.23 - 2.10 (t, 1H), 1.94 - 1.80 (t, 1H), 1.72 - 1.32 (t, 6H), 0.99 - 0.88 (t, 2H), 0.61 - 0.51 (t, 2H). MO-IER t/27 calc. 325.16534, found 326.3 (M.-1) same; Holding time: 1.9 min. (Method of RH B).

Stage 3: 3-IZ3-1-trifluoromethyl)cyclopropyl|propyl|pyrrolidin-2-one (6) (6) also ie, - -zhz

SEZ SEz

A 100 ml flask was charged under a nitrogen atmosphere with /1-benzyl-3-I3-(11- (trifluoromethyl)cyclopropyl|propyl|pyrrolidin-2-one (227 mg, 0.6977 mmol), propylamine (3 ml) and 1 ,2-ethanediamine (0.3 mL, 4.488 mmol). The mixture was cooled to -20 "C (external temperature of the cooling bath) and lithium (47 mg, 6.771 mmol) was added (the wire, which is briefly washed with hexane, then freshly cut into small pieces ).A blue color appeared around the small pieces of lithium, which then rapidly disappeared cyclically. After 20 minutes at -20 "C, the blue color became permanent. The reaction was quenched by adding methanol (400 μl) and water (10 ml) at -10 "C .

The product was extracted with ethyl acetate (2 x 25 ml). The combined organic extracts were dried over sodium sulfate and the solvents were evaporated to give crude material which was purified by flash chromatography on silica gel using a gradient of methanol (0-15 95 in 30 min) in dichloromethane to give 192 mg of crude material. This material was dissolved in ethyl acetate (30 mL) and the organic phase was washed with 0.1 N. hydrochloric acid (2 x 20 ml) and 1 n. hydrochloric acid (2 x 20 ml). Then the organic phase was dried over sodium sulfate, filtered and the solvents were evaporated to obtain 3-IZ-11-(trifluoromethyl)cyclopropyl|propyl|Ipyrrolidin-2-one (108 mg, 6695) as a white solid. IN NMR (400 MHz, chloroform-a) 5 5.76 (broadened c, 1H), 3.41-3.28 (m, 2H), 2.40-2.23 (m, 2H), 1.88 -1.73 (m, 2H), 1.67-1.44 (m, 4H), 1.42-1.30 (m, 1H), 0.97-0.90 (m, 2H), 0 ,61-0,47 (m, 2H).

MO-ER t/2 calc. 235.1184, found 236.2 (M'-1) k; retention time: 1.43 min. (Method of RH B).

Stage 4: (145)-12,12-dimethyl-8-(2-oxo-3-13-(1-

Zo (trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 174) and (145) -12,12-dimethyl-8-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo !| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 175) o b o

Me m y

SI M M from my 7 hear oh hear

MN MN

EzSo EzSs aiaztegeoteg 1 aiaz (egeoteg 2

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (100 mg, 0.2222 mmol), 3-I3-I1-trifluoromethyl)cyclopropyl|propyl|pyrrolidine-2 -one (54 mg, 0.2295 mmol),

Rag(aba)z (33 mg, 0.03604 mmol), xanthophos (21 mg, 0.03629 mmol), cesium carbonate (430 mg, 1.320 mmol), and anhydrous dioxane (1.5 mL). The mixture was bubbled with nitrogen for about 5 minutes (turned into a gel), closed and stirred at 120 "C for 14 hours.

The organic solvent was evaporated by blowing the ampoule with nitrogen. Then the reaction mixture was diluted with dimethyl sulfoxide (3 ml), subjected to microfiltration and subjected to reversed-phase preparative HPLC (C18) using a gradient of acetonitrile in water (from 1 95 to 99 95 in 15 min) and hydrochloric acid as a modifier (4 x 950 μl for injections, 400 μl).

Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Filtration followed by evaporation of the filtrate solvent resulted in 74 mg of a solid. Then the product was purified by flash chromatography on silica gel using a methanol gradient (from 095 to 5595 in 30 min) in dichloromethane to obtain a mixture of diastereomers, which was subjected to chiral separation by NCR (SpigaISe! 09U-N (250 x 10 mm), 5 μM column; mobile phase 22 95 acetonitrile/methanol (90:10, no modifier), 78 95 carbon dioxide, 10 mL/min; concentration 24 mg/mL in acetonitrile/methanol/dimethyl sulfoxide (85:9:6); injection volume 70 µl, 100 bar). The first eluted diastereomer was (145)-12,12-dimethyl-8-(2-oxo-3-(3-/1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-2A6-thia-3,9 . ) (Compound 174) (12.4 mg, 17 95). "IN NMR (400 MHz, DMSO-ab) b 12.39 (5, 1H), 7.67 (y, 9 - 8.4 Hz, 1H), 7.56 (Her, y - 7.9 Hz, 1H), 7.51 (a, Y - 8.5 Hz, 1H), 7.04 (a, - 7.1 Hz, 1H), 6.96 (Bgoaa a, U - 5.3 Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 4.04 (1,9) - 9.1 Hz . t, 2H), 2.31 - 2.19 (t, 1H), 2.10 (Brg 5, 1H), 1.87 - 1.66 (t, 4H), 1.64 - 1.22 (t, 15H), 0.92 - 0.83 (t, 2H), 0.76 - 0.68 (t, 2H). MO-IER t/: calc. 648.27057, found 649.5 (M--1)k; retention time: 2.14 min. (Method RH B). The second eluted diastereomer was (145)-12,12-dimethyl-8-(2-oxo-3-13-

P-"trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (compound 175) (12.2 mg, 17 90). IN NMR (400 MHz, dimethylsulfoxide-a 6) b 12.39 (5, 1H), 7.68 (y, U - 8.5 Hz, 1H), 7.63 - 7.48 (t, 2H), 7.04 (a, U - 7.1 Hz, 1H ), 6.95 (bha, in 2 5.1

Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 4.04 - 3.87 (t, 2H), 3.82 (d, U - 9.9, 9.0 Hz, 1H), 3.09 (Bgoaa 5, 1H), 2.94 ( y, U - 13.4 Gu, 1H), 2.75 - 2.61 (t, 2H), 2.24 (d, U - 8.7, 7.9 Hz, 1H), 2.17 - 1.96 (reg t, 1H), 1.87 - 1.64 (t, 4H ), 1.64 - 1.41 (t, 12Н), 1.41 - 1.15 (t, ЗН), 0.92 - 0.84 (t, 2Н), 0.71 (5, 2Н). MO-IER

From t/72 calc. 648.27057, found 649.4 (M'-1) k; Retention time: 2.12 min (method RH B).

Example 46: Preparation of 4-I3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6-thia-1,3,9, 14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (Compound 176 ) re vivr 1 vya vier2 be zier Z ON faith - -Vre, -VeR, Go--- (9) o) o. M o Z on N vivr 5 ak zierb o M, se vivr7 your aa av ovaya o r o du; us XX

M uv; Vier 8 se Ka, 0-5 U ke - kn- o - Moi - zivr9 y Y VosmM

II o o to Ge) zim? and Kk cha o vivr 10 0-5 Ma zivr 11 Mykh MM u she shcha - i. sun

Stage 1: 7-(bromomethyl)dispiro(|2.0.2.1|)heptane

A three-necked 1000-mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath, a dropping funnel, a .)-Ket temperature sensor, and a nitrogen inlet/outlet. Triphenylphosphine (102.7 mL, 443.2 mmol) and dichloromethane (1 L) were charged into the vessel under a nitrogen atmosphere, which gave a clear, colorless solution. Mixing begins and acetone is loaded into the cooling bath. Dry ice was added in portions to the cooling bath until the container temperature reached -157C. The dropping funnel was charged with a solution of bromine (22.82 mL, 443.0 mmol) in dichloromethane (220 mL, 10 mL/g), which was then added dropwise over 1 hour. Dry ice was added in portions to the cooling bath during the addition to maintain the vessel temperature at -15°C. After the bromine addition was complete, the pale yellow suspension was continued to stir at -157°C for 15 minutes, after which the suspension was cooled to -30°C. A solution of dispiro|2.0.2.1|heptan-7-ylmethanol (50 g, 402.6 mmol), pyridine (35.82 mL, 442.9 mmol), and dichloromethane (250 mL, 5 mL/g) was loaded into the dropping funnel. Then, a transparent pale yellow solution was added dropwise for 1.5 hours, maintaining the container temperature at -30 "C. The resulting transparent, light yellow reaction mixture was allowed to gradually heat up to the container temperature of -5 "C, and then stirring was continued at -5 "C for 1 hour. The reaction mixture was then poured into hexane (2000 mL), which resulted in the formation of a precipitate. The suspension was stirred at room temperature for 30 min and then filtered through a Buchner funnel with a 20 mm celite-lined glass frit. The clear filtrate was concentrated under reduced pressure (temperature of the water bath 20 "C) to obtain a yellow oil with some sediment. The oil was diluted with a small amount of hexane, kept at room temperature for 15 minutes and then filtered through a glass Buchner funnel with a 20 mm celite layer. The clear filtrate was concentrated under reduced pressure (water bath temperature at 20 "С) to obtain 7-(bromomethyl)dispiro(|2.0.2.1|heptane (70 g, 93 9o) in the form of a clear yellow oil. IN NMR (400 MHz, chloroform -4) b 3.49 (y, 9 - 7.5 Hz, 2H), 1.90 (1, U - 7.5 Hz, 1H), 1.06 - 0.84 (t, 4H), 0.71 (ada, 9 - 9.1, 5.1, 4.0 Hz, 2H), 0.54 (4aaa, U - 8.6, 4.6, 3.6, 1.0 Hz, 2H).

Stage 2: 2-dispiro|2.0.2.1|)heptan-7-ylacetonitrile

A three-necked 1000 mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary protective shell, a -Ket temperature sensor, and a nitrogen inlet/outlet valve. 7-

Zo(bromomethyl)dispiro|2.0.2.1|heptane (35 g, 187.1 mmol) and dimethylsulfoxide (245 mL), which gave a clear amber solution. Stirring was started and the temperature in the vessel was recorded at 19 C. Then, sodium cyanide (11.46 g, 233.8 mmol) was loaded into the vessel, added as a solid in one portion, which led to a dark solution and a gradual exothermic effect up to 49 "C for 15 min. After a few minutes, the vessel temperature began to decrease, and the mixture was continued to stir at room temperature overnight (about 15 h). The dark reaction mixture was quenched with ice-saturated saturated sodium carbonate solution (500 mL), then transferred to a separatory funnel and separated with diethyl ether (500 mL). The organic layer was removed and the remaining aqueous layer was extracted with diethyl ether (2 x 250 mL). The combined organic layers were washed with water (500 mL), dried over sodium sulfate (200 g), and then filtered through Buchner funnel with a glass frit. The clear amber filtrate was concentrated under reduced pressure (water bath temperature 20 "C) to obtain 2-dispiro(2.0.2.1|heptan-7-yl of acetonitrile (21 g, 84 95) in the form of a clear oil of dark amber color. 1H NMR (400 MHz, chloroform-a) 62.42 (d, 7 - 6.6 Hu, 2H), 1.69 (t, U - 6.6 Hz, 1H), 1.02-0.88 ( m, 4H), 0.79-0.70 (m, 2H), 0.66-0.55 (m, 2H).

Stage 3: 2-dispiro(2.0.2.1|)heptan-7-ylacetic acid /x les /x dl-. KON --A-63

F)

To a solution of 2-dispiro(2.0.2.1|heptan-7-ylacetonitrile (2.1 g, 14.19 mmol) in EUN (32 mL) was added sodium hydroxide (5.12 g, 128.0 mmol), then water ( 13 ml) and the resulting solution was stirred and heated to 70 "C overnight. Then the mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The aqueous phase was adjusted to pH - 1 by adding n. hydrochloric acid (which led to a cloudy precipitate) and extracted with diethyl ether (3). The organic phases were dried (magnesium sulfate), filtered and concentrated to give 2-dispiro(2.0.2.1|)heptan-7-ylacetic acid (2.19 g, yield 99 95, purity 9895) in in the form of an orange solid, which was used in the next stage without additional purification 1H NMR (400 MHz, chloroform-4) b 2.44 (a, 9 - 6.9 Hz, 2H), 1.67 (9 - 6.9 Hz, 1H), 0.91 (ada, 9 - 9.0, 5.2, 3.9 Hz, 2H), 0.81 (dada, o - 8.9, 5.2, 3.9, 0.5 Hz, 2H), 0.69 (ada, 9 - 8.9, 5.2, 3.9 Hz, 2H), 0.56 - 0.44 ( t, 2H).

Stage 4: 2-dispiro(2.0.2.1|)heptan-7-ylethanol /x a miracle /x -. iOH --- o

2-dispiro(2.0.2.1|)heptane- 7- acetic acid (2.552 g, 16.77 mmol) in tetrahydrofuran (7.470 ml) dropwise over 15 min, maintaining the reaction temperature at "20" C. The mixture was allowed to stir for a total of 18 h, gradually warming to ambient temperature. The mixture was cooled in an ice/water bath and quenched sequentially by slow addition of water (838.4 mg, 838.4 μL, 46.54 mmol), then sodium hydroxide (1.006 mL 5 M, 5.031 mmol), then water (2.493 g, 2.493 mL, 138.4 mmol) to obtain a white granular suspension, which was filtered through celite.

The filtered solid was washed with diethyl ether. The filtrate is concentrated in a vacuum at -300 mbar and a water bath of 30 "C. The residue was diluted with diethyl ether, dried (magnesium sulfate), filtered and concentrated in a vacuum at -"- 300 mbar and a water bath of 30 "C, and then seconds under vacuum to give 2-dispiro|2.0.2.1|heptan-7-ylethanol (2.318 g, 100 95), which was used directly in the next step without further purification. 1N

NMR (400 MHz, chloroform-4) b 3.64 (5, 2H), 1.68 (9, U - 6.7 Hz, 2H), 1.39 (5, 1H), 1.31 (5, 1H), 0.82 (a, U - 14.0 Hz, 4H), 0.65 (5, 2H), 0.50 (y, U - 3.6 Hz, 2H).

Stage 5: tert-butyl-3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazole-1-carboxylate o sv)

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To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (2.942 g, 15.97 mmol) and 2-dispiro|2.0.2.1|)heptan-7-ylethanol (2.318 g, 16.77 mmol) triphenylphosphine (4.399 g, 16.77 mmol) was added to tetrahydrofuran (36.78 mL). Diisopropylazodicarboxylate (3.391 g, 3.302 mL, 16.77 mmol) was slowly added dropwise to the mixture over 10 min (moderate exothermic effect was noted). The reaction mixture was stirred at room temperature for 30 minutes, then at 50 °C for 30 minutes.

The sediment gradually crystallized. After celite suspension, the sediment was filtered and washed with toluene (8.705 mL) and again with toluene (8.705 mL). The filtrate was concentrated by massio.

The crude product was purified by silica gel chromatography using a shallow gradient of 10095 hexanes to 10095 ethyl acetate to give tert-butyl 3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1-carboxylate (3.449 g, 7195) . MO-IER t/7 calc. 304.17868, found 305.1 (M--1)k; retention time: 0.82 min. (Method of RH A).

Stage 6: 3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)-1H-pyrazolomonohydrogenation

Tert-butyl-3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1-carboxylate (5.304 g, 17.43 mmol) was dissolved in dichloromethane (53.04 mL) with trifluoroacetic acid (29, 81 g, 20.14 ml, 261.4 mmol), and the reaction mixture was stirred at room temperature for 120 min.

The reaction mixture was evaporated, the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the layers were separated. The aqueous part was extracted two more times with ethyl acetate, then the organic layers were combined, washed with saline solution, dried over sodium sulfate, filtered and evaporated to obtain an oil, C (2-dispiro|2.0.2.1|heptan-7-ylethoxy)-1H pyrazole (3.56 g, 100 90). MO-IER t/: calc. 204.12627, found 205.1 (M--1)uc; retention time: 0.59 min. (Method of RH A).

Stage 7: tert-butyl 2-chloro-6-(3-(2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylate)

M, Chi (F) - --zh-zhd«- M y y; I oh- MM soi sim sei - what

Tert-butyl 2,6-dichloropyridine-3-carboxylate (4.322 g, 17.42 mmol), 3 (2-dispiro|2.0.2.1|heptan-7-ylethoxy)-1H-pyrazole (3.559 g, 17.42 mmol ) and potassium carbonate (2.891 g, 20.92 mmol) were combined in anhydrous dimethyl sulfoxide (71.18 mL). 1,4-diazabicyclo|2.2.2|octane (391.1 mg, 3.487 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (136.9 ml) and stirred for 15 min. The resulting white solid was filtered and washed with water.

The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give tert-butyl-2-chloro-6-(3-(2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylate (5.69 g , 79 95) in the form of a white solid substance. 1Н

NMR (400 MHz, Spiogoitogite-4) b 8.35 (y, y - 2.9 Hz, 1H), 8.18 (a, Y - 8.4 Hu, 1H), 7.69 (y, Y - 68.4 Hz, 1H), 5.94 (y, U - 2.9 Hz, 1H), 4.25 (5, 2H), 1.90 (a, U - 6.8 Hz, 2H), 1.62 (5, 9H), 1.49 (1, 7 - 6.6 Hz, 1H), 0.85 (a, 9 - 1.5 Hz, 4H), 0.65 (y, 9 - 1.5 Hz, 2H), 0.52 (y, U - 1.1 Hz, 2H). MO-IER t/: calc. 415.16626, found 360.0 (M-IVy) k; Holding time: 2.09 min. (Method of RH B).

Stage 8: 2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid 6) АХ 6) o- MI with soya 9- 0 M s

Tert-butyl 2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylate (5.85 g, 14.07 mmol) was dissolved in dichloromethane (58.5 mL) with trifluoroacetic acid (16.26 mL, 211.1 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and ether was added to the formed solid, and then the ether was removed under reduced pressure. This evaporation from ether was repeated twice more to give a white solid, 2-chloro-6-(3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-Z - carboxylic acid. (5.06 g, 10095). 1H NMR (400 MHz,

SNiogoiogt-a) b 8.41 (y, 9 - 8.5 Hz, 1H), 8.37 (a, Y - 2.9 Hz, 1H), 7.75 (a, Y - 8.5 Hz, 1H), 5.97 (y, y - 2.9 Hz, 1H), 4.27 (5, 2H), 1.91 (a, U - 6.7 Hz, 2H), 1.50 (5, 1H), 0.85 (a, U - 1.5 Hz, 4H), 0.71 - 0.62 (t, 2H), 0.52 (0.9 - 1.1 Hz, 2N). MO-IER t/2 calc. 359.10367, found 360.2 (Ma1)f; Holding time: 2.16 min. (Method of RH B).

Stage 9: tert-butyl 4-I3-I(3-(2-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazole-1-

Zo yl|pyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o o o Z. o o o

Us and; -8. 0-5 U Me x -- 0-5 Me i o i v.

BosM 2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (400 mg, 1.112 mmol) and carbonyldiimidazole (273.5 mg, 1.687 mmol) were combined in tetrahydrofuran (2 mL) and stirred for 90 min at room temperature. tert-Butyl-2,2-dimethyl-4-N3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (429.5 mg, 1.111 mmol) was then added, followed by 1,8-diazabicyclo/ 5.4.F)undec-7-ene (430.8 mg, 2.830 mmol), and the reaction mixture was stirred at room temperature for 1 h, then heated to 50 °C and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution sodium bicarbonate, and then saline.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl-4-13-3-(2-chloro-6- I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethyl pyrrolidin-1- carboxylate (350 mg, 43 95) as an off-white solid. TN NMR (400 MHz,

DdMSO-ab) b 8.34 (5, 1H), 8.08 (a, U - 8.2 Hz, 1H), 7.77 (5, 1H), 7.62 (a, U - 8.3 Hz, 1H), 6.71 - 6.49 (t, 1H ), 6.10 (a, U - 2.8 Hz, 1H), 4.23 (5, 2H), 4.13 (5, 2H), 3.52 (5, 1H), 2.73 (a, 9U - 6.0 Hz, 1H), 2.08 (a . ), 0.66 - 0.60 (t, 2H), 0.52 - 0.46 (t, 2H). MO-IER ip/2 calc. 727.2919, found 728.1 (Ma1) xx; retention time: 0.92 min. (Method of RH A).

Stage 10: 2-chloro-N-(1-3-(5,5-dimethylpyrrolidin-3-yl)propyl|pyrazol-3-yl|Isulfonyl-6-|3-(2-dispiro|2.0.2.1|heptane) -7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide o o o | chu -8 -5 cOogo cOoSo o-0 ke mm ----- w 9-0 M sei Mom y i y 4

Tert-butyl 4-3-3-(2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|pyrazole-1 -yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 0.4806 mmol) was dissolved in dichloromethane (1.527 mL) and trifluoroacetic acid (2.192 g, 1.481 mL, 19.22 mmol) was added to the mixture. and the resulting mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol to ensure solubility, and the layers were separated. The organic layer was concentrated by rotary evaporation followed by the use of a high vacuum pump , obtaining 2-chloro-M-11-I3-(5,5-dimethylpyrrolidin-3-yl)propyl|pyrazol-3-yl|Isulfonyl-6-3(2-dispiro(2.0.2.1|heptan-7-ylethoxy )pyrazol-1-yl|Ipyridine-3-carboxamide (301.9 mg, 100 95) in the form of an off-white solid. 1TN NMR (400 MHz, SOSIS) b 8.28 (y, Y - 2.68 Hz, 1H), 8.21 (а, 9 - 8.3 Hz, 1Н), 7.61 (а, - 8.3 Hz, 1H), 7.44 (5, 1H), 6.67 (5, 1H), 5.88 (8, U - 2.68 Hz, 1H), 4.22 (I, U - 6.68 Hz, 2H), 4.17 (5, 2H) . 1.35 (t, 5H), 1.35 - 1.24 (t, AN), 0.84 (Y, U - 1.9 Hu, 4H), 0.63 (y, U - 1.6 Hz, 2H), 0.51 (a, U - 1.1 Hz, 2H ).

Stage 11: 4-(3-(2-Isdispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3,9 ,14, 22-pentaazatetracycloi|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-

Zo trione (Compound 176 ) o oo Y chu -5 -8 сОгО СсОО

And d v

2-chloro-M-(1-(3-(5,5-dimethylpyrrolidin-3-yl)propyl|pyrazol-3-yl|isulfonyl-6-I(3-(2-dispiro|2.0.2.1 |heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-Z-carboxamide (310 mg, 0.4935 mmol), potassium carbonate (341.1 mg, 2.468 mmol), cesium fluoride (112.8 mg, 0, 7426 mmol), molecular sieves Z A and dimethylsulfoxide (9.3 ml) in a vial that was purged with nitrogen, closed with a lid, heated to 155"С and stirred for 20 hours. Cooled to room temperature, then the mixture was filtered, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic layers were separated, dried over sodium sulfate, evaporated, and then purified by chromatography on silica gel using a gradient of 100 F hexanes to 100 95 ethyl acetate to give 4-|3 as a white solid -(2-yldispiro(2.0.2.1|)heptan-7-ilyethoxy)-1H-pyrazol-1-yl|- 20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo/ 16.2.1.111,14.02,7 |docosa- 2,4,6,11(22),12-pentane-8 ,10,10-trione (compound 176) (117 mg, 40 95). IN NMR (400 MHz, SOSIZ) b 8.37 (5, 1H), 8.16 (a, 9 - 2.8 Hz, 1H), 7.68 (y, 9 - 8.3 Hz, 1H), 7.48 (a, U - 2.3 Hz, 1H ), 7.26 (5, 1H), 7.07 (a, - 2.3 Hz, 1H), 7.02 (a, 9 - 8.3 Hz, 1H), 5.86 (a, U - 2.8 Gu, 1H), 4.36 (j, U - 13.5 Hz, 1H), 4.24 (5, 2H), 3.95 (y, y - 12.4 Hz, 1H), 2.74 (1.9 - 8.1 Hz, 1H), 2.15 (a, 9U - 4.2 Hz, 2H), 2.08 - 1.93 (t,

ЗН), 1.89 (а, 9 - 6.7 Hz, 2Н), 1.76 (аа, У - 11.9, 5.3 Hz, 1Н), 1.59 (5, ЗН), 1.55 (5, 5Н), 0.85 (9, У - 2.0

Gu, 4H), 0.64 (a, U - 1.7 Hz, 2H), 0.51 (j, U - 1.2 Hz, 2H). MO-IER t/2 calc. 591.26276, found 592.4 (Ma-1) same; Holding time: 2.37 min. (Method of RH B).

Example 47: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1|Heptan-7-yl)ethyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6-thia-3 ,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( diastereomer 1) (Compound 177) and (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloyl 17.3.1. 111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 178) (c) (c)

B» ver, 1 B» nya St. Tera, Bo» zerz o o o n vier 4

Because" ov zmyM We -- l

МН b 9 о оо 5 5 и 7 и yesh 7 и

Cape Dove

MM I and M

МН МН аиаз(егеотег 1 аиаз(сегеотег 2

Stage 1: 7-(2-bromomethyl)dispiro(2.0.2.1|)heptane

B that B Vg

To a stirred solution of triphenylphosphine (1.07 g, 4.080 mmol) in anhydrous dichloromethane (15 mL) under a nitrogen atmosphere at -15" was added dropwise a solution of molecular bromine (0.22 mL, 4.271 mmol) in dichloromethane (3 mL) over 10 min. and upon completion of the addition (pale orange solution), the mixture was stirred for another 15 min at -15"С. The mixture was then cooled to -30 °C and a solution of 2-dispiro|2.0.2.1|heptan-7-ylethanol (537 mg, 3.885 mmol) and pyridine (330 μL, 4.080 mmol) in dichloromethane (4 mL) was added dropwise over 5 min, and upon completion of the addition, the mixture was heated to -57C and stirred for 2 hours. The reaction mixture was then poured into pentane (350 mL), resulting in a mass of yellow precipitate. This suspension was filtered and the filtrate was evaporated on a rotary evaporator (250 mbar and water bath 30 "C) to obtain a white solid. Pentane was added to this solid, the mixture was briefly sonicated and filtered. Concentration of this filtrate afforded 7-(2-bromomethyl)dispiro|2.0.2.1|heptane (634 mg, 81 95) as a pale yellow oil, which was used in the next step without any further purification. 1H NMR (400

MHz, chloroform-4a) b 3.37 (I, U - 7.1 Hu, 2H), 2.02 - 1.96 (t, 2H), 1.46 (I, 9 - 6.4 Hz, 1H), 0.91 - 0.78 (t, 4H), 0.66 (daa, U - 8.1, 4.8, 3.6 Hz, 2H), 0.50 (adaaa, U - 9.0, 4.9, 3.7, 0.9 Hz, 2H).

Stage 2: 1-benzyl-3-(2-dispiro|2.0.2.1|heptan-7-ylethyl)pyrrolidin-2-one o (e,;

B o Bo

Vg - MVp - - - t

A 100-ml flask was dried using a heat gun in a vacuum and filled with nitrogen. The flask was charged with 1-benzylpyrrolidin-2-one (0.46 mL, 2.875 mmol) and anhydrous tetrahydrofuran (5 mL). After cooling to -78 "С, a solution of n-butyllithium (1.3 ml, 2.5 M, 3.250 mmol) (2.5 M in hexane) was added dropwise, causing the formation of an orange solution. After stirring at -78 "С for A solution of 7-(2-bromomethyl)dispiro|2.0.2.1|)heptane (611 mg, 3.038 mmol) in tetrahydrofuran (1 ml) was added dropwise over 20 minutes. The mixture was stirred in a cooling bath, which was allowed to slowly warm to room temperature.

After 17 h, the mixture was quenched by adding saturated aqueous ammonium chloride (50 ml). The product was extracted with ethyl acetate (2 X 30 ml). The organic layer was dried over sodium sulfate,

filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100 95 over 30 min) in hexane. -2-one (352 mg, 41 95) as a colorless oil. IN NMR (400 MHz, Spiogotogt-a) b 7.38 - 7.17 (t, 5H), 4.45 (d, U - 14.7 Hz, 2H), 3.22 - 3.10 (t, 2H), 2.42 (da, U - 8.68, 4.1 Hz, 1H), 2.21-2.07 (t, 1H), 2.00 - 1.85 (t, 1H), 1.62 (ad, U 2 12.7, 8.4 Hz, 1H), 1.51 - 1.42 (t, 2H), 1.42 - 1.25 ( t, 2H), 0.88 - 0.71 (t, 4H), 0.68 - 0.55 (t, 2H), 0.51 - 0.39 (t, 2H). MO-IER t/2 calc. 295.1936, found 296.3 (M.-1) k; Holding time: 2.08 min. (Method of RH B).

Stage 3: 3-(2-dispiro|2.0.2.1|heptan-7-ylethyl)pyrrolidin-2-one (c) c)

Because BA

1-benzyl-3-(2-dispiro|2.0.2.1|heptan-7-ylethyl)pyrrolidin-2-one (350 mg, 1.185 mmol), propylamine (4 ml) and 1 ,2-ethanediamine (510 μL, 7.629 mmol). The mixture was cooled to -20 "C (temperature of the external cooling bath) and lithium (72 mg, 10.37 mmol) was added (wire briefly washed with hexane, then freshly cut into small pieces). A blue color appeared around the small pieces of lithium, which then quickly disappeared. After 2 hours at -20 "C, the blue color became permanent. The reaction was quenched by the addition of methanol (400 μl) at -20 "С and water (40 ml). After heating to room temperature, the white solid in the suspension was filtered, washed with water and briefly dried in air (200 mg). The material was purified by flash chromatography on silica gel using a methanol gradient (from 0 to 1595 in 30 min) in dichloromethane to give 3-(2-dispiro|2.0.2.1|heptan-7-ylethyl)pyrrolidin-2-one (173 mg, 71 95) as a white of a solid substance. TNA NMR (400 MHz,

SNiogoiogt-a) b 5.69 (Bgoai 5, 1H), 3.41 - 3.24 (t, 2H), 2.37 - 2.20 (t, 2H), 1.88 (aidaa, 9 - 13.4, 9.1, 7.4, 3.8 Hz, 1H), 1.83 - 1.67 (t, 1H), 1.53 - 1.41 (t, 2H), 1.41 - 1.29 (t, 2H), 0.86 - 0.74 (t, 4H), 0.67 - 0.59 (t, 2H), 0.51 - 0.39 (t, 2H). MO-IER t/: calc. 205.14667, found 206.2 (Ma-1) t; Holding time: 1.61 min. (Method of RH B).

Stage 4: (145)-8-I3-(2-idispiro(2.0.2.1|)heptan-7-yl)ethyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3 ( diastereomer 1) (Compound 177) and (145)-8-I3-(2-idispiro|2.0.2.1|heptan-7-yl)ethyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6 -thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 178) ooo

KU o zi ZM xx

SI M M -60--

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Ki Mu sva sheatse

MM m where I am MM cm My

МН МН аиазиегеотег 1 аиазиеегеотег 2

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)htetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (100 mg, 0.2222 mmol), 3-(2-dispiro(2.0.2.1|heptan-7-ylethyl )pyrrolidin-2-one (47 mg, 0.2289 mmol),

Rag(ara)Z (32 mg, 0.03495 mmol), xanthophos (19 mg, 0.03284 mmol), cesium carbonate (365 mg, 1.120 mmol), and anhydrous dioxane (1.5 mL). The mixture was purged with nitrogen for approximately 5 minutes, capped, and stirred at 120 °C for 16 hours. The organic solvent was evaporated by purging the vial with nitrogen. The reaction mixture was diluted with dimethyl sulfoxide (3 mL), subjected to microfiltration, and subjected to reversed-phase preparative HPLC (C18) with using a gradient of acetonitrile in water (1 to 99 95 in 15 min) and hydrochloric acid as a modifier. The pure fractions were collected and the organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporation of the solvents gave a residue which was purified by flash chromatography on silica gel using a gradient of methanol (0 to 5 95 in 30 min) in dichloromethane.The resulting product was dissolved in dimethyl sulfoxide (2 mL) and further purified by preparative HPLC using a gradient of acetonitrile in water from 50 to 99 95 over 15 min (hydrochloric acid as modifier.) Pure fractions were collected and evaporated organic solvents. The resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporation of the solvents gave a diastereomeric mixture, which was subjected to NCR separation (SpPPigaibeI 09U-H (250 X 10 mm), 5 µM column; mobile phase 2495 acetonitrile/methanol (90:10, without modifier), 7695 carbon dioxide, 10 ml/min; concentration 24 mg/ml in a mixture of acetonitrile/methanol/dimethylsulfoxide (72:8:20); injection volume 70 μl, 100 bar). Fractions of the pure product were combined, the solvents were evaporated and the residue was triturated in dichloromethane/hexane. The first eluted diastereomer was (145)-8-

13-(2-idispiro|2.0.24.13)heptan-7-yl)ethyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 177) (6, 3 mg, 9 to). IN NMR (400 MHz, DMSOO-ab) b 12.38 (5, 1H), 7.67 (9, U - 8.5 Hz, 1H), 7.62 - 7.45 (t, 2H), 7.03 (y, U - 7.2 Hz, 1H) , 6.95 (bgoaay 5, 1H), 6.70 (a,

U 8.7 Hu, 1H), 4.04 (I, U - 8.9 Hz, 1H), 3.91 (Bg aa, U - 25.4, 13.2 Hu, 1H), 3.74 (d, U - 9.0, 8.4 Hu, 1H), 3.11 ( Bg 5, 1H), 2.94 (rga, U - 13.5 Hu, 1H), 2.76 - 2.63 (t, 1H), 2.64 - 2.54 (t, 1H), 2.22 (d, 9 - 9.0, 8.2 Hz, 1H), 2.10 (Bg 5, 1H), 1.92 - 1.63 (t, 4H), 1.64 - 1.18 (t, 14H), 0.89 - 0.70 (t, 4H), 0.68 - 0.57 (t, 2H), 0.53 - 0.39 (t, 2H). MO-IER t/2 calc. 618.2988, found 619.5 (M--1)k; Holding time: 2.37 min. (Method of RH B). The second eluted diastereomer was (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethyl)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (compound 178) (5,2 mg, 7 90). 1 H NMR (400 MHz, dimethylsulfoxide-ya 6 ) b 12.38 (5, 1H), 7.67 (a, 9U - 8.5 Hz, 1), 7.62 - 7.45 (t, 2H), 7.03 (a, U - 7.0 Hu, 1H), 6.95 (Brgoai 5, 1H), 6.70 (a, U - 68.6 Hz, 1H), 3.93 (I, U - 9.3 Gu, 2H), 3.82 (d, U - 9.9, 8.9 Hz, 1H), 3.10 (Bg 5, 1H), 2.93 (Bga, U - 13.0 Gu, 1H), 2.76 - 2.55 (t, 2H), 2.31 - 2.17 (t, 1H), 2.09 (re 5, 1H), 1.86 - 1.63 (t , 4H), 1.61 - 1.29 (t, 14H), 0.86 - 0.73 (t, 4H), 0.67 - 0.58 (t, 2H), 0.51 - 0.40 (t, 2H). MO-IER t/27 calc. 618.2988, found 619.5 (M-- 1); Retention time: 2.37 min (method RH B).

Example 48: Preparation of (145)-8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|I-12,12-dimethyl-2Ab-thia- 3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-

Of 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 179) and (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!yl 17.3.1. 111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 180) o io)

BM I with ve, Be; And in / ov is I

SI M SI

(c) o (c) e-0 ke zer Z o dk SHY "un dra

Sho) o c o we, o so 9 ss M- vir 5 | - n M MN zier 6 pla feu ex

Y et Y "2noi red o om o 0.0 o om?

Y Y Yaiaziegeoteg 1 Y Diaziegeoteg 2

Stage 1: 3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrrolidin-2-one o (c) one and)

Bai that Bai S many more MN 7

2-dispiro(2.0.2.1|heptan-7-ylethanol (502 mg, 6595 wt., 2.361 mmol)) (containing 3595 wt./wt. of residual tetrahydrofuran), 3-bromopyrrolidine-2- (390 mg, 2.378 mmol) and anhydrous tetrahydrofuran (12 mL). The mixture was cooled to -50 °C, then (Ibis(trimethylsilyl)amino|potassium (10 mL of 0.5 M in toluene, 5.000 mmol)) was added dropwise and the mixture was stirred at -50 "C for 15-20 min, then in an ice bath at 0 C for 3 hours. The reaction mixture was allowed to slowly warm to room temperature (pink reaction mixture). After 14 h, the mixture was cooled to 0 "C, then to to the reaction mixture was added glacial acetic acid (210 μL, 3.693 mmol), yielding an orange suspension. Brine (75 mL) and ethyl acetate (75 mL) were added, and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x25 mL). The combined the organic extracts were dried over sodium sulfate, filtered, and the solvents were evaporated.The crude residue was purified by chromatography on silica gel (0-15 96 methanol in a gradient of dichloromethane for 30 minutes) to obtain the desired 3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrrolidin-2-one (399 mg, 76 95) as pale - orange resin, which slowly hardened. TN NMR (400

MHz, DMSO-46) b 7.74 (Bgoaay 5, 1H), 3.84 (aa, 9 - 7.7, 7.1 Hz, 1H), 3.71 (a, y - 9.2, 6.7 Hz, 1H), 3.44 (a, - 9.3, 6.68 Hz, 1H), 3.22 - 3.01 (t, 2H), 2.27 (ai, U - 12.8, 7.4, 3.7 Hz, 1H), 1.78 (da - 12.8, 8.4, 7.1 Hz, 1H), 1.57 (d, U - 6.7 Hz, 2H), 1.35, 9 - 6.6 Hz, 1H), 0.87 - 0.70 (t, 4H), 0.67 - 0.55 (t, 2H), 0.54 - 0.36 (t, 2H). MO-IER t/2 calc. 221.14159, found 222.2 (Ma1)f; retention time: 1.35 min. (Method of RH B).

Stage 2: tert-butyl 2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)-2-oxo-pyrrolidin-1-yl|pyridine-3-carboxylate (9) p and their seam, r o new as far as smt c

A 100 mL flask was charged with tert-butyl 2,6-dichloropyridine-3-carboxylate (424 mg, 1.709 mmol) and 3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrrolidine-2 -one (376 mg, 1.699 mmol) in anhydrous M,M-dimethylformamide (4 mL). Potassium carbonate (724 mg, 5.239 mmol) (325 mesh) was added followed by 1,4-diazabicyclo(2.2.2)octane (62 mg, 0.5527 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 16 h, the reaction was quenched by adding water (50 ml), and then extracted with ethyl acetate (3 x 40 ml).

The organic phase was dried over sodium sulfate, filtered and volatile substances were evaporated.

The product was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 5095 over 30 min) in hexane. The pure fractions were collected and the solvents evaporated to give tert-butyl 2-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl|pyridine-3-carboxylate (555 mg, 75 95) in the form of a colorless resin. TN NMR (400 MHz, DMSO-

ZB ab)b 8.33 (a, 9 - 68.6 Hz, 1H), 8.24 (a, 9 - 8.6 Hz, 1H), 4.32 (aa, 9 - 8.8, 7.9 Gu, 1H), 4.07 - 3.94 (t, 1H) . , U - 6.7 Hz, 2H), 1.55 (5, 9H), 1.39 (I, U - 6.6 Hz, 1H), 0.88 - 0.71 (t, 4H), 0.69 - 0.57 (t, 2H), 0.46 (0, 9 - 8.8 Hz, 2H). MO-IER t/2 calc. 432.18158, found 433.3 (Ma); retention time: 2.43 min. (Method of RH B).

Stage 3: 2-chloro-6-3-(2-dispiro|2.0.2.1)heptan-7-ylethoxy)-2-oxo-pyrrolidin-1-yl|pyridine-3-carboxylic acid

(9) ХХ (Ф) - --- -- captured M' sei

Tert-butyl 2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)-2-oxo-pyrrolidin-1-yl|pyridine-3-carboxylate was introduced into a 100 ml vial (533 mg, 1.231 mmol), dichloromethane (5 mL), and trifluoroacetic acid (1.4 mL, 18.17 mmol) (color rapidly changed to brown). The mixture was stirred at room temperature for three hours. The reaction mixture was diluted with dichloromethane and hexane, and the volatiles were evaporated under reduced pressure. The residue was triturated with dichloromethane/hexane and the volatiles were evaporated (the cycle was repeated 3 times) to give 2-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-ylethoxy)-2-oxo-pyrrolidin-1- yl|pyridine-3-carboxylic acid (479 mg, yield 103 95, purity 93 95) as a pale gray solid. 1H NMR (400 MHz, DMSO-ab) b 13.51 (5, 1H), 8.34 (a, U - 68.6 Hz, 1H), 8.31 (a, U - 8.5 Hz, 1H), 4.32 (9 - 8.3 Hu, 1H), 4.01 (aa, U - 11.2, 8.68, 2.8 Hu, 1H), 3.88 - 3.63 ( t, 2H), 3.56 (ai, U - 9.3, 6.7 Hz, 1H), 2.47 - 2.37 (t, 1H), 1.89 (ad, U - 12.2, 8.6 Hz, 1H), 1.62 (d, U - 6.7 Hz , 2H), 1.39 (her, U - 6.5 Hz, 1H), 0.93 - 0.69 (t, 4H), 0.69 - 0.56 (t, 2H), 0.46 (a, U - 8.6 Hz, 2H). /: calcd 376.119, found 377.1 (M--1) gk, retention time: 1.83 min (Method RH B).

Stage 4: tert-butyl (45)-4-III-C(6-Ce-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)-2-oxo-pyrrolidine-1 -yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate ooo

Eat them B U o se he ny h se Me e- My bo o My her

Vos-M s i Y zad

2-Chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carboxylic acid was charged into a 100 ml round-bottomed flask under a nitrogen atmosphere (475 mg, 1.261 mmol) and anhydrous tetrahydrofuran (8 ml). Carbonyldiimidazole (225 mg, 1.388 mmol) (freshly recrystallized from tetrahydrofuran) was added and the mixture was stirred under nitrogen at room temperature for 2. Another 150 mg of carbonyldiimidazole was added and the mixture was stirred at room temperature for 2 hours. In a separate 20 ml flask, a solution of tert-butyl (45)-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (520 mg, 1.260 mmol) in anhydrous tetrahydrofuran (4 mL) was obtained under a nitrogen atmosphere and subsequently added via syringe to a solution of the activated ester.1,8-diazabicyclo/5.4.O1undec-7-ene (0.95 mL, 6.353 mmol) was added via syringe and the reaction mixture stirred at room temperature under a nitrogen atmosphere overnight.After 18 h

The solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (30 mL) and water (30 mL). Aqueous hydrochloric acid (1.4 ml 6 M, 8.400 mmol) was slowly added (final pH - 5) and the two phases were separated. The aqueous phase was extracted again with ethyl acetate (30 ml).

The combined organic extracts were washed with saline (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue (1.34 g) was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100 95 over 30 minutes) in hexane to give the still crude product. This material was further purified by flash chromatography on silica gel using a gradient of ethyl acetate (from 0 to 10095 over 30 minutes) in hexane to give tert-butyl (45)-4-IZ-Cb-C2 //-chloro-6-IZ-( 2-dispiro|2.0.2.1|heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylIamino|propyl|-2,2- dimethylpyrrolidine-1-carboxylate (449 mg, 46 95) in the form of a white foamy solid. MO-

IER t/2 calc. 770.3229, found 771.5 (M--1) xx; retention time: 2.43 min. (Method of RH B).

Stage 5: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridylI|sulfonyl|-6-I3-(2-dispiro|2.0. 2.1|heptan-7-ylethoxy)-2-oxo-pyrrolidin-1-yl|pyridine-3-carboxamide (dihydrochloride salt)

oooh oooh

U u h M no U " I M no a, M sei MN u, ke MN : y: Chen -2Нsi

Tert-butyl (45)-4-IZ3-C6-C2-chloro-6-I(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl) was loaded into 100 ml |Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2- dimethylpyrrolidine-1-carboxylate (440 mg, 0.5704 mmol), dichloromethane (5 mL) and hydrochloric acid (800 μL 4 M in dioxane, 3.200 mmol). The reaction was stirred at room temperature for nearly 3 h. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexane and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in vacuo gave 2-chloro- M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl/|-6-(3-(2-dispiro|2.0.2.1|heptane-7 -ylethoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (453 mg, 107 95) as a white solid. The product was used in the next step without further purification. 1H NMR (400 MHz, DMOO -ab) b 12.75 (Bgoaay 5, 1H), 9.12 (re 5, 1H), 8.99 (horn 5, 1H), 8.32 (a, U - 8.5 Hz, 1H), 8.02 (aa, U - 8.5, 0.8 Hz, 1H), 7.61 (aa, U - 8.5, 7.2 Hz, 1H), 7.26 (Bg 5, 1H) 7.19 - 7.11 (t, 1H), 6.75 (ai, U - 8.5, 0.7 Hz, 1H), 4.32, 9 - 8.3 Gu, 1H), 3.97 (Id, U - 8.8, 8.3, 4.7 Hz, 1H), 3.84 - 3.65 (t, 2H), 3.56 (a, y - 9.2, 6.7 Hz, 1H), 3.35-3.28 (t, 1H) 3.29 - 3.15 (t, 2H), 2.88 - 2.73 (t, 1H), 2.49 - 2.25 (t, 2H), 1.98 - 1.81 (t, 2H), 1.62 (d, U - 6.7 Hz, 2H), 1.56 - 1.44 (t, ЗН), 1.44 - 1.33 (t, 6Н), 1.28 - 1.26 (t, ЗН), 0.82 - 0.76 ( t, 4H), 0.68 - 0.57 (t, 2H), 0.53 - 0.39 (t, 2H). MO-

IER t/2 calc. 670.27045, found 671.4 (M--1) k; retention time: 1.65 min. (Method of RH B).

Stage 6: (145)-8-I3-(2-Isdispiro(2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3, 9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione o | )

To u type (o) tim sh (o) | M me r N M - N MN

And editor and "NS

2-Chloro-M-(6-I3-((35)-5,5-dimethylpyrrolidin-Z-yl|Ipropylamino|-2-pyridyl|sulfonyl| -6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl|pyridine-3-carboxamide (dihydrochloride salt) (446 mg, 0.5993 mmol), anhydrous MMR (25 mL), anhydrous potassium carbonate (615 mg, 4.450 mmol) (325 mesh). The mixture was vigorously stirred in a dry bath at 150 °C under nitrogen for 14 h, then at 155 °C for 3 h, then at 160 C for 3.5 hours. After cooling to room temperature, the mixture was poured into cold water (200 mL) and acidified by adding aqueous hydrochloric acid (1.5 mL, 6 M, 9,000 mmol) (slight foaming). The resulting solid was filtered and briefly dried in air. The solid was dissolved in dichloromethane and the resulting opaque solution was decanted to remove the remaining water and dried over sodium sulfate. After concentration, the residue was purified by flash chromatog. raffia on silica gel using a methanol gradient (from 0 to 5 9o in 30 min) in dichloromethane. Evaporation of the solvents followed by trituration in dichloromethane/lexanes and evaporation of the solvents gives (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclol 1 7.3. 1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4--rione (198 mg, 52 95) as a white solid. MO-IER t/2 calc. 634.29376, found 635.4 (Ma1) xx; retention time: 2.17 min. (Method of RH B).

Stage 7. (145)-8-I3-(2-Isdispiro(2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3, 9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (di( astereomer 1) (Compound 179) and (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 180)

to / oo, in ro with

І and diazygeoteg 1 І adiazivegeoteg 2 (145)-8-(3-(2-yIdispiro|2.0.2.1|heptan-7-yl)iethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab -thia- 3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2, The 4-rione (200 mg, 0.3088 mmol) was subjected to chiral separation by NKR chromatography using a Spiga!Rak 0-H column (250 X 10 mm) (particle size 5 μm) with a mobile phase of 20 95 acetonitrile/methanol (90:10)/80 95 carbon dioxide at 10 ml/min for 8.0 min injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/umethanol/dimethyl sulfoxide (85:9:6)), which gives in qualities of the first eluted diastereomer (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (compound 179) (86 mg, 43 95,» 98 95 ee) in the form of a white solid, 1H NMR (400 MHz, DMSO-ab6) b 12.43 (5, 1H), 7.70 (a, U - 8.4 Hz, 1H), 7.57 (da, U - 8.5, 7.2 Hz, 1H), 7.51 (a,

In same 8.4 Hu, 1H), 7.04 (a, U - 7.1 Hz, 1H), 6.96 (y, U - 9.0 Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 4.22, 9 - 7.9 Hu . 9 - 10.5, 7.5 Hz, 1H), 3.55 (ai, U - 9.2, 6.7 Hz, 1H), 3.18 - 3.06 (t, 1H), 2.94 (0.9 -13.2

Hu, 1H), 2.76 - 2.62 (t, 1H), 2.40 (49, 9 - 12.3, 7.2, 2.9 Hz, 1H), 2.18 - 2.01 (t, 1H), 1.97 - 1.86 (t, 1H), 1.82 ( aa, U - 12.1, 5.4 Hu, 1H), 1.79 - 1.68 (t, 1H), 1.62 (d, y - 6.7 Hu, 4H) (asishayPu eat igiriei5, 2 X 2H), 1.57 (v, ZN), 1.55 - 1.49 (t, 1H), 1.46 (5, ZN), 1.38 (I, U - 6.5 Hu, 1H), 1.30 - 1.23 (t, 1H), 0.84 - 0.77 (t, 4H), 0.67 - 0.57 (t , 2H), 0.50 - 0.41 (t, 2H); MO-IER t/2 calc. 63429376, found 635.4 (М-а-1)х; Retention time: 2.19 min (method RH B); and as the second eluted diastereomer (145)-8-3-(2-(dispiro|2.0.2.1|heptan-7-yl)ethoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b -thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trione (diastereomer 2) (compound 180) (76 mg, 38 95, 98 90 ee) as a white solid; 1H NMR (400 MHz, dimethylsulfoxide-ab) b 12.41 (5, 1H), 7.70 (a, 9 - 8.5 Hu, 1H), 7.57 (I, Y - 7.9 Hz, 1H), 7.52 (9, Y - 8.4 Hz , 1H), 7.04 (y, 9 - 7.2 Hz, 1H), 6.96 (5, 1H), 6.70 (9.9 - 8.5 Hz, 1H), 4.27 (1.9 - 8.2 Hz, 1H), 3.91 (y , U - 9.9 Hz, 2H), 3.78 (I, - 8.2 Hz, 2H), 3.54 (d, U - 8.2 Hz, 1H), 3.14 - 3.04 (t, 1H), 2.98 - 2.89 (t, 1H), 2.72 - 2.63 (t, 1H), 2.16 - 2.03 (t, 1H), 1.89 - 1.72 (t, ЗН), 1.61 (pmo iiriviv, 2 X 2Н), 1.57 (v, ЗН), 1.53 - 1.48 (t, 1H), 1.46 (5, ЗН), 1.41 - 1.35 (t, 1H), 1.35 - 1.19 (t, 2H), 0.83 - 0.76 (t, 4H), 0.62 (y, U - 8.9 Hz, 2H), 0.46 (a, 9 - 68.68

From Hz, 2H); MO-IER t/2 calc. 634.29376, found 635.4 (M'-1)xk; Holding time: 2.18 min (method

RK B).

Example 49: Preparation of (145)-12,12-dimethyl-8-13-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-2Ab-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (Compound 185)

Ge Gei | he about

Х , - vivr 1 SI all vivr2 zivr Z and AK vivr4

SI SI de e) kiKoK M. Ge) o sim soi (e) (e) - 7 4 on che

M... 2 | M. that si na" and believe 8 0-5 ke zier 7 o i shk Ma. » o Y t le ooo 7 9 given vace

M "M nok. viere he m Mach

MM Te -- 7

DY - zOshshe al

Stage 1: 1-chloro-2,2,3,3-tetramethyl-1-(1,2,2-trichlorovinyl)ucyclopropane

SI SI

SI SI Sat-

X in - - 5 - 5" and 1 SI

SI SI

2,3-dimethylbut-2-ene (20.5 mL, 172.5 mmol) and 1,2,3,3-tetrachlorocyclopropene (29.1 g, 163.6 mmol) were added to a microwave-safe vessel. The reaction flask was hermetically closed and heated at 155"C for 16 hours. The reaction mixture was cooled to room temperature and transferred to a flask. The crude reaction mixture was distilled from flask to flask in a vacuum at 1957C to obtain // 1-chloro-2,2, 3,3-tetramethyl-1-(1,2,2-trichlorovinyl/ucyclopropane) (37.49 g, 87 95) in the form of an orange liquid. NMR (400 MHz, chloroform-4) 6 1.25 (s, ЗН ), 1.22 (s, ZN), 1.20 (s, ZN), 1.18 (s, ZN).

Stage 2: 3-ethynyl-1,1,2,2-tetramethylcyclopropane

SI SI

Si -

Si - -1- -

1-chloro-2,2,3,3-tetramethyl-1-(1,2,2-trichlorovinylcyclopropane (17.4 g, 66.41 mmol) and diethyl ether (300 ml) were added to a 500 ml round-bottom flask. The reaction mixture was cooled to -78 "C and stirred for 15 minutes. A solution of n-butyllithium (118 mL of 2.5 M, 295.0 mmol) was added dropwise over 30 minutes and the mixture was allowed to warm to room temperature for 2 hours and additionally stirred at room temperature for 1 hour. The reaction mixture was cooled to -10 "C and water (35 mL, 1.943 mol) was added dropwise and the mixture was allowed to stir and warm to room temperature for 30 minutes. The reaction mixture was extracted with ether, dried over sodium sulfate , filtered and evaporated. The crude reaction mixture was purified by distillation at 80 "C in a vacuum, obtaining 3-ethynyl-1,1,2,2-tetramethylcyclopropane (6.059 g, 7595). 1H NMR (400 MHz, chloroform-4) b 1 .96 (d, u) - 2.2 Hz, 1H), 1.11 (d, U - 3.68 Hz, 12H), 0.86 (d, U - 0.9 Hz, 1H).

Stage 3: 2-(2,2,3,3-THetramethylcyclopropyl)ethanol

And K

3-ethynyl-1,1,2,2-tetramethylcyclopropane (4.1 g, 33.55 mmol) and tetrahydrofuran (25 mL) were added to a dry round-bottom flask. The reaction mixture was cooled in a -30 "C bath for 5 minutes. A solution of borane in tetrahydrofuran (33.6 ml of 1 M, 33.60 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature for 30 minutes. The reaction mixture was cooled to - 10 "C and cautiously added sodium hydroxide (28.5 mL, 6 M, 171.0 mmol), followed by hydrogen peroxide (38 mL, 30 95 wt./vol., 335.1 mmol). The reaction mixture was allowed to stir for 30 minutes while warming to room temperature.

The reaction mixture was extracted with ether, dried over sodium sulfate, filtered and evaporated to give the crude intermediate aldehyde. Methanol (40 mL) was added to the crude aldehyde. The reaction mixture was cooled to 0 "C and sodium borohydride (2.54 g, 67.14 mmol) was added in portions. The reaction mixture was allowed to stir for 1 h when heated to room temperature. The reaction was quenched with a solution of saturated ammonium chloride and saline and extracted with ether The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-(2,2,3,3-tetramethylcyclopropyl)ethanol (1.800 g, 38 95) as an oil. 1TN NMR (400 MHz, Spiogothogitt-a) b 3.64 (I, U - 6.9 Hz, 2H), 1.54 (d, U - 7.0 Hz, 2H), 1.06 (5, 6H), 0.93 (5, 6H), 0.13 (U - 7.1 Hz, 1H). t/2 calculated 142.13577, found 143.1 (Ma1)k Retention time: 1.49 min (Method RH B).

Stage 4: tert-butyl 3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazole-1-carboxylatone (e) (o)

N. Z. M. D. Z

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (884 mg, 4.799 mmol) and 2-(2,2,3,3-tetramethylcyclopropyl)ethanol (650 mg, 4.570 mmol) in tetrahydrofuran (10 ml) triphenylphosphine (1.26 g, 4.804 mmol) was added. Diisopropylazodicarboxylate (970 mg, 4.797 mmol) was slowly added dropwise to the mixture over 2 minutes at room temperature (exothermic effect noted). The reaction mixture was stirred at room temperature for 30 min. The tetrahydrofuran was removed in vacuo, toluene (30 mL) was added and the mixture was stirred overnight. No precipitate was observed and the mixture was evaporated and purified by chromatography on silica gel (gradient from 0 956 to 50 95 ethyl acetate in hexane) to give tert-butyl-3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazole- 1-carboxylate (700 mg, 50 95). 1 H

Zo NMR (400 MHz, Spiogoitogit-a) b 7.82 (y, Y - 2.9 Hz, 1H), 5.86 (y, Y - 2.9 Hz, 1H), 4.27 1.9 - 7.2 Hz, 2H), 1.72 (4, 9 - 7.2 Hz, 2H), 1.61 (5, 1OH), 1.05 (5, 6H), 0.95 (5, 6H), 0.22 (Y, U - 7.2 Hz, 1H). MSO-IER t/2 calc. 308.21, found 309.24 (M.-1)k; Holding time: 0.89 min. (Method of RH A).

Stage 5: 3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazole ()

M. r XX M

Sodium hydroxide (2, 35 mL of 2 M, 4,700 mmol), and the mixture was stirred at ambient temperature for 30 minutes.

Most of the methanol was removed by vacuum and the residue was diluted with water (14 mL) and aqueous hydrochloric acid (4.5 mL of 1 M, 4.500 mmol). The mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated as a pale yellow oil, 3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazole (471 mg, 10095) which was used directly in the next step MO-IER t/: calcd 208.15756, found 209.2 (Ma1)k Retention time: 1.77 min (RC Method E).

Stage 6: ethyl 2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|pyridin-3-carboxylate () 2 in: shdh-khu ol» 0 -7 "M M SI and I se o i (Fi M ss

Ethyl 2,6-dichloropyridine-3-carboxylate (494 mg, 2.245 mmol), 3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazole (471 mg, 2.261 mmol) and carbonate potassium (373 mg, 2.699 mmol) was combined in anhydrous dimethyl sulfoxide (10 mL).1,4-diazabicyclo(|2.2.2|octane (50.5 mg, 0.4502 mmol) was added and the mixture was stirred at room temperature in under nitrogen for 20 h. The reaction mixture was diluted with water (16 mL) and stirred for 15 min. The resulting white solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over sodium sulfate. The mixture was filtered and evaporated to give a dirty -white solid ethyl-2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylate (800 mg, 91 95). 1Н

NMR (400 MHz, Spiogoitogit-4) b 8.36 (y, y - 2.9 Hz, 1H), 8.27 (a, 9U - 8.4 Hz, 1H), 7.72 (a, y - 8.5 Hz, 1H), 5.97 (y, U - 2.9 Hz, 1H), 4.41 (d, y - 7.2 Hz, 2H), 4.254419 - 7.2 Hz, 2H), 1.77 (ad, - 7.2 Hz, 2H), 1.42 (4.9 - 7.2 Hz, ЗН) , 1.08 (5, 6Н), 0.97 (5, 6Н), 0.25 (1, 9 - 7.2 Hz, 1Н). MO-IER t/2 calc. 391.16626, found 392.2 (M--1)k; retention time: 2.25 min. (Method of RH E).

Stage 7. 2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid o (c) 7 o» and OH o - oh oh

Ethyl 2-chloro-6-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|pyridine-3-carboxylate) (800 mg, 2.041 mmol) in tetrahydrofuran (4.000 mL ) and ethanol (1600 mL) were treated with sodium hydroxide (2.0 mL 2 M, 4.000 mmol) and the solution was stirred at room temperature for 1 h. Most of the solvent was removed under reduced pressure and the solution was acidified by slowly adding citric acid (8.0 mL , 10 95 wt./vol., 4.164 mmol) under ice cooling. The thick suspension (- pH - 3) was stirred in an ice bath for 1 h, filtered and washed with excess water. The collected solid was completely dissolved in dichloromethane, dried over sodium sulfate , filtered and concentrated to dryness, using toluene as an azeotrope, and then dried under vacuum for 21 h to obtain 2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazole-1- il|Ipyridine-3-

From carboxylic acid (710 mg, 96 95) as a white solid. 1H NMR (400 MHz, DMSO-ab) b 13.56 (5, 1H), 8.52 - 8.29 (t, 2H), 7.72 (0, U - 8.4 Hz, 1H), 6.18 (9.9 - 2.8 Hz, 1H) ,4.234.9 - 6.8 Hz, 2H), 1.72 (d, U - 7.0 Hz, 2H), 1.04 (5, 6H), 0.95 (5, 6H), 0.27 (I, U - 7.2 Hz, 1H).MS - IER t/7 calc. 363.13498, found 364.2 (M.-1) k; retention time: 2.35 min. (Method РХ 0).

Stage 8: tert-butyl (45)-4-III-C6-Ce-chloro-6-I(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|Ipyridin- 3-carbonyl|Isulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (c) (o) in: x

Z y M y o-mb township. MO) verv m. plot 7 - eight Mach -Щ- 0-5 M sei 2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|Ipyridin- 3-Carboxylic acid (255 mg, 0.7009 mmol) and carbonyl diimidazole (125 mg, 0.7709 mmol) were combined in tetrahydrofuran (5.738 mL) and stirred for 90 min at room temperature.

Tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (350 mg, 0.8484 mmol) was added, followed by anhydrous 1,8 -diazabicyclo|5.4.FOundec-7-ene (275 μl, 1.839 mmol) and the reaction mixture was stirred at room temperature for 20 h.

The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and then with saline. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure, then purified by chromatography on silica gel using a gradient from 100 90 hexanes to 80 Fo ethyl acetate in hexane to obtain tert-butyl (45)-4-IT3-( (6-Ce-chloro-6-I3-(2-(2,2,3,3- tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2- pyridylyamino|Ipropyl|-2 ,2-dimethylpyrrolidine-i-carboxylate (261 mg, 4995) as a white solid. MO-IER t/2 calcd. 757.3388, found 758.5 (M--1)k; retention time: 2.43 min. (Method RH C).

Stage 9: (145)-12,12-dimethyl-8-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl-2Ab-thia-3, 9,11,18,23-pentaazatetracyclo!17.3.1.111,14.05,10|tetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (Compound 185 ) y 9 D. chuya zier sh U M. 9-0 ZM y -y 9-0 МОm y Y LI y y y

Tert-butyl (45)-4-IZ3-Cb-C(2-chloro-6-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|pyridin-3- carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (115 mg, 0.1516 mmol), potassium carbonate (125 mg, 0.9045 mmol), molecular sieves Z A and dimethyl sulfoxide ( 4 ml) were combined in a vial, purged with nitrogen, closed with a lid, heated to 160C and stirred for 72 hours. Cooled to room temperature. The mixture was filtered and the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with saline. Organic the layers were separated, dried over sodium sulfate and evaporated, then purified by silica gel chromatography using a gradient of 100 95 hexanes to 70 95 ethyl acetate in hexane to give (145)-12,12-dimethyl-8 -13-(2- (2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-2Ab6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111 ,14.05,10|hetrakose-1(23),5(10), of 6,68,19,21-hexane-2,2,4-trione

Zo (compound 185) (18.14 mg, 1995). IN NMR (400 MHz, Spiogoitogit-4a) b 9.96 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 8.07 (a, U - 8.3 Gu, 1H), 7.60 - 7.49 (t, 2H) , 7.36 - 7.23 (t, 2H), 6.56 (a, U - 8.0 Gu, 1H), 5.92 (a,

U - 2.9 Hz, 1H), 4.82 - 4.58 (t, 1H), 4.2541.9 - 7.2 Hz, 2H), 4.00 - 3.76 (t, 1H), 3.35 (I, U - 8.8 Gu, 1H), 3.17 ( 9, U - 14.3 Hz, 1H), 3.07 (I, U - 9.8 Hz, 1H), 2.73 - 2.50 (t, 1H), 2.09 (aa, 9 - 12.3, 7.9 Hz, 1H), 1.76 (d, U - 7.1 Hz, 2H), 1.65 - 1.59 (t, 6H), 1.53 - 1.41 (t, 2H), 1.08 (5, 6H), 0.97 (v, 6H), 0.90 - 0.81 (t, 2H), 0.25 ( I, 9 - 7.2 Hz, 1H). MO-IER t/ calc. 621.30975, found 622.2 (Ma-1)k; Holding time: 2.22 min. (Method of RH B).

Example 50: Preparation of (185)-4-3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6-thia-1 ,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7 |docosa- 2,4,6,11(22),12-pentane-8,10,10-trione (Compound 187)

Fo to nal? x on? y o zer1 Y o - i e si zivr2

VosM VosmM Y a 9 IT du ooo she, That zivr Z v-0s shchi and that zivr4 o- ev and their u o y

Stage 1: tert-butyl (45)-2,2-dimethyl-4-I3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidin-1-carboxylate odde)oo

TV TV

NM" GO nom" x

VosM VosM

Racemic tert-butyl 2,2-dimethyl-4-(3-(3-sulfamoylpyrazol-1-yl)upropyl|Ipyrrolidine-1-carboxylate (3.24 g, 8.383 mmol) was subjected to chiral separation using

NCR chromatography using SpigaIRak IS (column 250 X 21.2 mm, particle size 5 μm) with 28 95 methanol/72 o carbon dioxide as the mobile phase at 70 ml/min for 14.0 min (injection volume - 500 μl of a solution of 32 mg/ml in methanol to obtain the second eluted enantiomer, tert-butyl (45)-2,2-dimethyl-4-I3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (1.45 g, 90 95). IN NMR (400 MHz, SOSIZ) b 7.42 (y, U - 2.4 Hz, 1H), 6.72 (9.9 - 2.5

Hu, 1H), 5.08 (5, 2H), 4.22 - 412 (t, 2H), 3.64 (i, U - 9.1 Hz, 1H), 2.80 (I, U - 10.68 Hu, 1H), 2.05 (5, 1H ), 1.99 - 1.80 (t, ZN), 1.58 (5, 1H), 1.45 (a, U - 2.3 Gu, 9H), 1.40 (j, U 2 11.4 Hz, 4H), 1.27 (5, AN).

MO-ER t/2 calc. 386.19876, found 3871 (M--1)k; retention time: 1.52 min. (Method of RH B).

Stage 2: tert-butyl (45)-4-(3-III3-Ce-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3 -carbonyl|sulfamoyl|pyrazol-1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Mom | m si same 0-0 M si h-M o 06066220

Y VosM with /

BosM 2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (1.35 g, 3.752 mmol) and carbonyl diimidazole (761, 1 mg, 4.694 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether and dried under high vacuum) was combined in tetrahydrofuran (17.55 mL) and stirred for 50 min at room temperature. Then tert-butyl (45)-2,2-dimethyl-4-I3-(3-sulfamoylpyrazol-1-yl)/propyl|pyrrolidine-1-carboxylate (1.45 g, 3.752 mmol) in tetrahydrofuran (6.75 ml), then 1,8-diazabicyclo/5.4.O0)undec-7-ene (2.857 g, 18.77 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Tetrahydrofuran was removed using a rotary evaporator, dissolved in ethyl acetate and washed with a saturated aqueous solution of ammonium chloride (1X), then with brine (1X), dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a reversed-phase column 27594 C18 with a gradient from 50 to 100 95 acetonitrile/water. The product was eluted as in pure

From fractions and in mixed fractions with the original acid. Pure fractions were united,

concentrated, then distributed among b n. hydrochloric acid and ethyl acetate. The layers were separated, the aqueous layer was washed again with ethyl acetate, then the organic phases were combined, dried (sodium sulfate), filtered and concentrated to a white solid. The mixed fractions from the reverse phase column were combined and concentrated under reduced pressure.

The remainder was distributed among hydrochloric acid and ethyl acetate. The layers were separated, the aqueous layer was washed again with ethyl acetate, then the organic phases were combined, dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a reversed-phase column with 275 g of C18, eluting with a gradient from 50 to 100 95. acetonitrile/water. Pure fractions were combined, concentrated and added to the purified material from the first column to obtain tert-butyl (45)-4-(3-IZ-Ce-chloro-6-|3-(2-dispiro|2.0.2.1|heptane) -7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (1.96 g, 72 95). IN NMR (400 MHz, SOSIZ) b 9.50 (5, 1H), 8.30 (a, U - 2.9 Hz, 1H), 8.26 (a, U - 8.5 Hz, 1H), 7.75 (a, U - 8.5 Hz, 1H) . - 7.1 Hz, 2H), 3.66 (5, 1H), 2.83 (I, U - 10.6 Hz, 1H), 2.06 (a, U - 9.7 Hu, 1H), 1.90 (p, U - 7.2 Hu, 5H), 1.48 (1.9 - 6.7

Hu, 2H), 1.44 (5, 9H), 1.37 (5, ЗН), 1.35 - 1.29 (t, 2Н), 1.26 (5, ЗН), 0.87 - 0.82 (t, 4Н), 0.69 - 0.64 (t, 2H), 0.51 (a, 9 - 8.8 Hz, 2H). MO-IER t/2 calc. 727.2919, found 728.1 (Ma1)f; retention time: 0.91 min. (Method of RH A).

Stage 3: 2-chloro-M-(1-IZ-K(35)-5,5-dimethylpyrrolidin-3-yl|Ipropyl|pyrazol-3-yl|Isulfonyl-6-|3- (2-dispiro|2.0 .2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide o o, o o, xx 78. xx 75. t MSS -- I 5 t M' SS

VosmM NM

Tert-butyl (45)-4-I3-(3-Ce-chloro-6-I3-(2-dispiro|(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-

C-Carbonyl|Isulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (1.96 g, 2.691 mmol) was dissolved in dichloromethane (8.553 mL) and trifluoroacetic acid (8.291 mL, 107.6 mmol), and the mixture was stirred at room temperature for 60 minutes.

The mixture was concentrated to dryness under reduced pressure, treated with a saturated aqueous solution of sodium bicarbonate and ethyl acetate containing a little methanol to ensure solubility, and the layers were separated. The organic layer was concentrated on a rotary evaporator with subsequent use of a high-vacuum pump, obtaining 2-chloro-M-/1-I3-(35)-5,5-dimethylpyrrolidine-

Z-yl|Ipropyl|pyrazol-3-yl|Isulfonyl-6-I3-(2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-

Z-carboxamide (1.84 g, 109 95) as a yellow solid. MO-IER t/l calc. 627.23944, found 628.1 (M.-1) k; retention time: 0.65 min. (Method of RH A).

Stage 4: (185)-4-3-(2-(dispiro(2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3 ,9,14 22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 187) o o o o o o o o o o xx V.

NM

Combined 2-chloro-M-(1-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropyl|pyrazol-3-yl| sulfonyl-b-

3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (1.69 g, 2.690 mmol), potassium carbonate (1.859 g, 13.45 mmol), cesium fluoride (614.9 mg, 4.048 mmol), molecular sieves Z

A and dimethyl sulfoxide (102.5 ml) in a vial, purged with nitrogen, closed with a lid, heated to 155 "C and stirred for 18 hours. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with brine solution. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 100 95 ethyl acetate to obtain (185)-4-|3- (2-I( dispiro|2.0.2.1|heptan-7-ylylethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02, 7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (compound 187) (1.14 g, 72 95). IN NMR (400 MHz, DMSO-ab) b 12.69 (5, 1H), 8.17 (j, 9 - 2.8 Hz, 1H), 8.00 (a, 9 - 2.3 Hz, 1H), 7.71 (a, 9 - 8.2 Gu, 1H), 6.91 - 6.84 (t, 2H), 6.06 (y, 9 - 2.7 Hz, 1H), 4.21 (da, U - 7.2, 6.6, 2.7 Hz, ЗН), 4.13 (ai, y - 13.7, 11.3 Hz, 1H), 2.72 - 2. 62 (t, 1H), 2.09 (a, U - 12.0 Hz, 2H), 1.94 - 1.84 (t, 1H), 1.84 - 1.75 (t, 5H), 1.55 (5, ЗН), 1.47 (5, ЗН) . , 4.2 Hz, 2H). MO-IER tp/2 calc. 591.26276, found 592.1 (M--1)k; retention time: 2.34 min. (Method of RH B).

Example 51: Preparation of 8-13-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo! 17.3.1.111,14.05,10|)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 189)

Me in o-i, vyvr 1 oi, zivr2 g gak on (is) (o) o o, o x Mach Vosm M t o ! nM- E AH Am in poyu bo

M. to her M cher 5 M. 4 M

Stage 1: tert-butyl 2, 2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate c)

M o v: shcha gla

M hak t c) on

To a solution of tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.0 g, 3.885 mmol) in dichloromethane (25 mL) was slowly added Dess-Martin periodate (2.0 g, 4.715 mmol) at 0 "C under a nitrogen atmosphere. The resulting heterogeneous reaction mixture was slowly warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with diethyl ether and filtered through a pad of celite. The filtrate was concentrated and the residue was purified through a short plug of silica gel using a mixture of hexanes and ether 1:11 to obtain tert-butyl-2,2-dimethyl-4-(3Z-oxopropyl)pyrrolidine-1-carboxylate (992 mg, 100 95) in the form of a colorless viscous oil. 2 calcd 255.18344, found 256.2 (M--1)k Retention time: 0.64 min (RC method

AND).

Stage 2: tert-butyl 2,2-dimethyl-4-3-(methylamino)propyl|pyrrolidine-1-carboxylate c) vi o a

M o-i ha on x HnM-- (F)

To a solution of tert-butyl-2,2-dimethyl-4-(33-oxopropyl)pyrrolidine-1-carboxylate (500 mg, 1.958 mmol) in dichloromethane (10 mL) was added sodium acetate (241 mg, 2.938 mmol), and then

Zo methylamine (1.2 mL of 2 M, 2.400 mmol). The reaction mixture was stirred at room temperature for 1 hour, cooled to 0 °C, and sodium cyanoborohydride (372 mg, 5.920 mmol) was added under a nitrogen atmosphere. The heterogeneous reaction mixture was slowly warmed to room temperature and stirred for another 16 hours. The reaction mixture was quenched with water and slowly extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reversed-phase HPLC-MS using a double gradient of 20-80 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile to obtain /tert-butyl-2,2-dimethyl-4-III-(methylamino)propyl|pyrrolidine-1-carboxylate (154 mg, 29 95 ) in the form of a viscous oil. "IN NMR (400 MHz, Spiogotogit-a) b 3.80 - 3.53 (t, 1H), 3.04 - 2.81 (t, ЗН), 2.69 (d, y - 4.68 Hz, ЗН), 2.13 (5, 1H), 1.89 (5, ЗН), 1.80 (5, 2H), 1.45 (а,

In - 10.5 Hz, 12H), 1.38 (5, 2H), 1.29 (5, ZN). MO-IER t/2 calc. 270.23074, found 271.3 (Ma1)хk; Holding time: 0.47 min. (Method of RH A).

Stage C: tert-butyl 2,2-dimethyl-4-3-(methyl(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate oo

M o V o on Us

НнМ-- Oh and

To a solution of tert-butyl-2,2-dimethyl-4-3-(methylamino)propyl|pyrrolidine-1-carboxylate (154 mg, 0.5695 mmol) in dimethyl sulfoxide (2 mL) was added b-fluoropyridine-2 sulfonamide ( 103 mg, 0.5847 mmol) followed by diisopropylethylamine (500 μL, 2.871 mmol). The flask was closed with a septum and heated at 90 "C in a nitrogen atmosphere (balloon) in an oil bath for 14 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by chromatography on silica gel using a gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl-2,2-dimethyl-4-(3-

Imethyl(b-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate (141 mg, 58 95) as a white solid. 1H NMR (400 MHz, DMSO-ab) 5 7.65 (da, 9 - 8.6, 7.2 Hz, 1H), 7.12 (5, 2H), 7.01 (a, 9 - 7.2 Hz, 1H), 6.78 (a, U - 8.7 Hz, 1H), 3.53 (d, y - 7.6, 7.4 Hz, ЗН), 3.17 (а, У - 3.6 Hz, 1Н), 3.04 (5, ЗН), 2.84 - 2.72 (t, 1Н), 2.09 ( a, U - 9.5 Gu, 1H), 1.88 (4, U - 12.8, 5.7 Hz, 1H), 1.53 (a, U - 14.6, 7.4 Hz, 2H), 1.36 (da, 9 - 15.0, 10.6 Hz, 14H ), 1.23 (5, ZN). MO-IER t/2 calc. 426.23007, found 427.3 (M--1) k; retention time: 0.47 min. (Method of RH A).

Stage 4: tert-butyl 4-I3-(6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridyl|-methyl -amino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate?

Zo In a scintillation vial with a volume of 20 ml, 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (141 mg, 0.3858 mmol) and carbonyldiimidazole (65 mg , 0.4009 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 2 hours at room temperature. Then tert-butyl-2,2-dimethyl-4-I3-(methyl(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate) (134 mg, 0.3141 mmol) was added followed by the addition of 1, 68-diazabicyclo|5.4.F)undec-7-ene (100 μl, 0.6687 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:11 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated.

The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100 95 dichloromethane to 20 95 methanol in dichloromethane to give tert-butyl 4-I3-C6-Ce-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazole-1 -yl|pyridine-3-carbonyl|isulfamoyl|-2-pyridyl|methylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (158 mg, 65 95) as a white solid. TN NMR (400 MHz, Spiogoitogt-a) b 8.29 (y, y - 2.8 Hz, 1H), 7.98 (a, Y - 8.4 Hu, 1H), 7.77 - 7.60 (t, 2H), 7.52 (F, 9 - 7.2 Hz, 1H), 6.64 (a, U - 8.6 Hz, 1H), 5.98 - 5.91 (t, 1H), 4.42 (a, U - 8.3, 6.8 Hz, 2H), 4.14 - 4.04 (t, 1H), 3.91 (a, U - 13.9 Hz, 1H), 3.32 - 3.21 (t, 1H), 3.01 (5, ЗН), 2.91 (Y, 9 - 10.7 Gu, 1H), 2.18 (a, U - 12.8 Hz, 1H ), 2.02 - 1.93 (t, 2H), 1.79 (9, U - 16.6, 14.4, 6.6 Hz, 2H), 1.65 - 1.48 (t, 2H), 1.37 (5, 9H), 1.30 (5, ЗН), 1.25 (5, ЗН), 1.22 - 1.14 (t, 2Н), 0.67 (yes, 9 - 13.3, 6.7, 3.6 Hz, 2Н), 0.49 - 0.39 (t, 4Н), 0.37 - 0.30 (t, 1Н), 0.23 - 0.17

(t, 2H), 0.10 (aa, U - 9.4, 5.1, 4.5, 2.3 Hz, 2H). MO-IER t/: calc. 769.3388, found 770.45 (MA1) k; Holding time: 0.67 min. (Method of RH A).

Stage 5: 8-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!| 17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 189) o o o o in VO in M

Tert-butyl 4-I3-C(6-C2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|isosulfamoyl|-2-pyridyl|methyl-amino) solution |Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (153 mg, 0.1986 mmol) in dichloromethane (1.2 mL) and trifluoroacetic acid (150.0 μL, 1.960 mmol) was stirred at room temperature for 4 h. Then the solvents were removed under vacuum. The residue was dissolved in ethyl acetate, washed with 2 mL of saturated sodium bicarbonate solution, the solvent was removed and dried under high vacuum. The resulting residue was dissolved in dimethyl sulfoxide (8 mL), 4A molecular sieves were added, and the reaction mixture was stirred for 10 min Then, cesium fluoride (98 mg, 0.6451 mmol) and potassium carbonate (91 mg, 0.584 mmol) were added, and the reaction mixture was heated at 130 °C overnight. , and the filtrate was purified by the method

Reverse-phase HPLC-MS using a double gradient of 20-80 95 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) To obtain 8-IZ3-( 3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10 |)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 189) (76 mg, 6095) as an off-white solid. 1TN NMR (400 MHz, Spiogoitogit-4) b 10.54 (5, 1H), 8.19 (y, U - 2.8 Hz, 1H), 8.13 (a, U - 8.4 Hz, 1H), 7.67 (da, U - 8.6, 7.3 Hz, 1TN), 7.60 - 7.54 (t, 1Н), 7.37 (а, У - 8.4 Hz, 1Н), 6.69 (ad, 9 - 8.7, 0.68 Hz, 1Н), 5.92 (а, У - 2.68 Hz, 1H), 4.43 (I, U - 6.8 Hz, 2H), 4.37 (5, 1H), 3.37 (49, 9 - 9.6, 7.2 Hz, 1H), 3.13 - 3.05 (t, 1H), 3.01 (5, ZN ), 2.87 (a, U - 26.3 Hz, 1H), 2.24 (da, U - 12.5, 91 Hz, 1H), 1.97 (d, U - 6.8 Hz, 2H), 1.70 (5, 1H), 1.65 (5 ) ), 0.34 (aaa, U - 15.9, 9.0, 6.9 Hz, 1H), 0.23 - 0.16 (t, 2H), 0.15 - 0.07 (t, 2H). MO-IER t/:2 calc. 633.30975, found 634.22 (Ma1)k; Holding time: 1.55 min. (The method of RH U).

From Example 52: Preparation of (14K)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia -3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4- trionu (Compound 194) 9. che MI what else uvof

Mykh zier 1 Ma M. -

In Ot ve ra 7 She --erh ooo ooo b oo no I no AKA i o- M te Z ver o- M ss mo ver 0-5 m ZU in -- Vosm mn - NM Mn - sho: and zosh I

Stage 1: tert-butyl (4K)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate and

НМ 5 nom 5

M. U M a

Racemic tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (7 g, 16.97 mmol) was subjected to chiral separation using NKR-

chromatography using SpPigaIRak IS (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 40 95 methanol/b0 95 carbon dioxide at 70 ml/min for 11.0 min (injection volume - 500 μl of solution 32 mg/ml in methanol as the second eluted enantiomer of tert-butyl (4K)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (3.167 g, 90 90) MO-IER t/72 calculated 412.21442, found 413.2 (M i 1) zhk, retention time: 0.63 min (RCA method).

Stage 2: tert-butyl (4K)-4-I3-C(6-Ce-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridin- 3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate 9 o ooo 2 | | M i not o o- and in Mom still in. mon ny ry Ge! and sheep: in for both

To a solution of 2-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (1.95 g, 5.420 mmol) in tetrahydrofuran ( 20 mL) was added carbonyldiimidazole (1.03 g, 6.073 mmol) and the mixture was stirred at ambient temperature for 1 h. To this mixture was added tert-butyl (4K)-2,2-dimethyl-4-IZ-K(b -sulfamoyl-2-pyridyl)amino|propyl|Ipyrrolidine-1-carboxylate (1.95 g, 4.301 mmol) in tetrahydrofuran (9 mL), then 1,8-diazabicyclo(/5.4.0)undec-7-ene ( 2.0 mL, 13.37 mmol), and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (50 mL) and the mixture was acidified with hydrochloric acid (5 mL 6 M, 30.00 mmol). The mixture was extracted with ethyl acetate (200 mL) and the organic phase was separated The organic phase was washed with brine and the combined aqueous phases were back extracted with 50 mL of ethyl acetate.

The combined organic phases were dried over magnesium sulfate, filtered and concentrated by massio.

The obtained crude product was chromatographed on a reversed-phase column with 275 g of C18, eluting with a mixture of 50-100 95 acetonitrile/water. The product fractions were collected and concentrated in vacuo, obtaining tert-butyl (4K)-4-I3-(6-C2-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazole-1- yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2- dimethylpyrrolidine-1-carboxylate (2.73 g, 65,965) NMR (400 MHz, DMSO-46) b 12.76 (5, 1H), 8.38 (I, U - 2.3 Hz, 1H), 8.11 (a, 9 - 8.3 Hz, 1H), 7.70 (a, 9 - 8.3 Gu, 1H), 7.62 (da, U - 8.5, 7.2 Hz, 1H), 7.18 (aa, U - 12.6, 6.3 Hz, 2H), 6.74 (a, U - 8.5 Hz, 1H), 6.16 (ai, 9 - 2.9, 1.4 Hz, 1H), 4.24 (I, In - 6.6

Gu, 2H), 3.57 - 3.44 (t, 1H), 3.24 (1.9 - 6.0 Hz, 2H), 2.74 (I, U - 10.5 Hz, 1H), 2.01 (Ш, y - 11.9, 6.5

Hz, 1TN), 1.82 (d, U - 6.6 Hz, ZN), 1.49 (1, U - 13.0, 6.9 Hz, ZN), 1.36 (a, U - 11.6 Hz, 10OH), 1.33 - 1.24

Koo) (t, 6H), 1.17 (5, ЗН), 0.89 - 0.75 (t, 4H), 0.71 - 0.60 (t, 2H), 0.54 - 0.44 (t, 2H). MO-IER t/: calc. 753.30756, found 754.4 (M.-1); retention time: 3.69 min. (Method РХ 0).

Stage 3: 2-chloro-M-((6-I3-KZNA)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|- 6-I3-(2-dispiro|2.0.2.1 |heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-Z-carboxamide (trifluoroacetate salt) 7 dme 0 om th m Ex Ex m? xx

M | Ж n M d M Ж M 4 0-5 u m s -- - 0-5 M s - 0 Vosm MN - Nm MN

Ov "TBA KI

To the solution tert-butyl (4K)-4-I3-(6-C2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl To isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (2.73 g, 3.619 mmol) in dichloromethane (15 mL) and toluene (5 mL) was added trifluoroacetic acid (3 mL, 38 .94 mmol) and the mixture was stirred at ambient temperature for 48 h. The solvent was removed in vacuo at a bath temperature set at 45 °C to give a thick yellow oil. The oil was diluted with toluene (20 mL) and the solvent was removed in vacuo at bath temperature , set at 45 "С, obtaining 2-chloro-M-I((6-IZ-KZA)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-6-(3- (2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) (2.78 g, 100 95) as an oil, which was used without further purification. TN NMR ( 400

MHz, DMSO-ab) 5 12.78 (5, 1H), 8.61 (5, 2H), 8.39 (a, y - 2.9 Hz, 1H), 8.11 (a, 9 - 8.4 Hz, 1H), 7.71

(a, 9 - 8.3 Hz, 1H), 7.63 (aa, 9 - 8.5, 7.2 Hz, 1H), 7.34 - 7.11 (t, 5H), 6.75 (da, U - 8.6, 0.7 Hz, 1H), 6.18 ( a, 9 - 2.9 Hz, 1H), 4.24 (1, 9 - 6.7 Hu, 2H), 3.36 (y, 9 - 11.6, 6.1 Hz, 1H), 3.25 (4.9 - 6.6 Hu, 2H), 2.89 - 2.71 (t, 1H), 2.30 (5, 2H), 1.93 (aa, U 2 12.9, 7.6 Hz, 1H), 1.89 - 1.71 (t, 2H), 1.48 (d, 9 - 7.2, 6.3 Hz, 4H) . MO-IER t/2 calc. 653.2551, found 654.3 (M--1)f; retention time: 2.49 min. (Method РХ 0).

Stage 4: (14K)-8-I3-(2-(dispiro(2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9 ,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 194 ) ooo ooo

MI МХ/ сх м"? тх Ме м"? sx pra MK ky 9-5 MOSS -- A - F 5-5 MOM -d- NM MN - S ln

To the solution of 2-chloro-M-((6-I(3-(ZA)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-6-(3-(2-dispiro| Potassium carbonate (2.5 g, 18 ,09 mmol).

The mixture was carefully acidified with hydrochloric acid (7 mL of 6 M, 42.00 mmol) to give a foamy suspension. The solid was collected by filtration using a medium size frit. The wet precipitate on the filter was dissolved in ethyl acetate (200 ml), washed with 100 ml of saline solution, then concentrated in vacuo. The crude product was diluted with acetonitrile and chromatographed on a C18 250 g reversed-phase column, eluting with a mixture of 500-100 F water/acetonitrile, to obtain a foam, which was dried in a vacuum oven at 4570 for 48 hours, obtaining (14K)-8-I3-( 2-I(dispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloi| 17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 194) (1.3 g, 57 90 ). "IN NMR (400 MHz, DMSO-ab) b 12.51 (5, 1H), 8.20 (y, U - 2.68 Hz, 1H), 7.62 (a, U - 8.3 Hu, 1H), 7.58 (da, U - 8.5 , 7.2 Hz, 1H), 7.05 (a, 9 - 7.2 Hz, 1H), 6.99 (a, U - 8.9 Hz, 1H), 6.91 (a, 9 - 8.2 Gu, 1H), 6.71 (a, U - 8.4 Hz, 1H), 6.09 (a, U - 2.7 Hz, 1H), 4.21 (Id, 7 - 6.6, 1.4 Hz, 2H), 3.92 (y, U - 11.8 Gu, 1H), 3.15 (5, 1H), 2.95 (а, 9 13.2

Hu, 1H), 2.78 - 2.64 (t, 1H), 2.12 (5, 1H), 1.90 - 1.70 (t, 4H), 1.60 (5, 6H), 1.51 (5, ЗН), 1.47 (1.9 - 6.5 Hz , 1H), 1.31 (d, U - 12.0 Hu, 1H), 0.89 - 0.78 (t, 4H), 0.70 - 0.61 (t, 2H), 0.55 - 0.44 (t, 2H).

From MO-0ER t/» calc. 617.27844, found 618.4 (M--1) zhk; retention time: 3.38 min. (Method РХ 0).

Example 53: Preparation of (145)-8-IZ3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3 ,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( Compound 195) (e) o, | Fu 8 - in Nom Go M soya Z cher2

M. 2 M vier 1 and shk shko) zer, for ma V -- and ee she you ooo y: m? y: Zh m". z na ev (4 stars "MM M o NM Mn " o Zv "TRA AL --

Stage 1: tert-butyl (45)-4-I3-C(6-Ce-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridin- 3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

(c) 9 o oo i Tone on what ss Go pe soya A U o fen oi ony ni speech

To a solution of 2-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (5.2 g, 14.45 mmol) in carbonyl diimidazole (2.8 g, 16.51 mmol) was added to tetrahydrofuran (100 mL) and the mixture was stirred at ambient temperature for 1 h. tert-butyl (45)-2,2-dimethyl-4-I3 was added to this mixture -(b-sulfamoyl-2-pyridyl)amino|propyl|Ipyrrolidine-1-carboxylate (6.0 g, 14.54 mmol) in tetrahydrofuran (15 mL), then 1,8-diazabicyclo/5.4.0)undec- 7-ene (6.5 mL, 43.47 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (150 mL) and the mixture was acidified with aqueous hydrochloric acid (15 mL, 6 M, 90.00 mmol).

The mixture was extracted with ethyl acetate (300 ml) and the organic phase was separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered through Celite and concentrated in vacuo to give a white precipitate. The precipitate was suspended in acetonitrile, the solid was collected by filtration using a medium-sized glass frit and washed with acetonitrile. The filtrate was concentrated in vacuo to give a yellow oil.

The crude oil was diluted with acetonitrile and some M-methyl-2-pyrrolidone and chromatographed on a C18 column of 415 g with a reverse phase, eluting with 50-100 95 acetonitrile in water, obtaining tert-butyl (45)-4-I3-((6- Ce-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2- Dimethylpyrrolidine-1-carboxylate (4.5 g, 41 95), MO-IER t/2 calcd 753.30756, found 754.4 (Ma1) xx, retention time: 3.79 min (RC Method 0).

Stage 2: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridylI|sulfonyl|- 6-I3-(2-dispiro|2.0. 2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-Z-carboxamide (trifluoroacetate salt) p oo by 5 m?

M | - n Y - M | 2 N M - -- Eight MN -- NM MN kV LLEA KI

To the solution tert-butyl (45)-4-I3-C(6-C2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3 -carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (5.9 g, 7.821 mmol) in dichloromethane (30 ml) and toluene (15 ml) was added trifluoroacetic acid (6, 0 ml, 77.88 mmol) and the mixture was stirred at ambient temperature for 18 h. The solvent was removed in vacuo at room temperature

The oil was diluted with toluene (125 mL) and the solvent was removed by mass at a bath temperature set at 450. The oil was diluted with toluene and the solvent was removed by mass to give a thick viscous oil. yellow, 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-6-|(3- (2-dispiro| 2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) (6.0 g, 100 95), which was used in the next step without further purification. MSO-IER t/72 calcd 653.2551, found 654.3 (M--1) k, retention time: 2.6 min (Method RH B).

Stage 3: (145)-8-IZ3-(2-(dispiro(2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9 ,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 195 ) o oo M chu lan SOS - NM MN -d- MN i sh I i

Zoo

To the solution of 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl sulfonyl|-6-3-(2-dispiro|2.0.2.1| )heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (6.0 g, 7.810 mmol) in MMP (140 mL) was added potassium carbonate (5.3 g, 38.35 mmol ). The mixture was purged with nitrogen for 5 min. The mixture was then heated at 150 "С for 22 h. The reaction mixture was cooled to room temperature and added to water (300 mL), obtaining an off-white solid precipitate. The mixture was carefully acidified with aqueous hydrochloric acid (12 mL of 6 M, 72.00 mmol) to give a foamy suspension. The solid was collected by filtration using a medium-sized glass frit. The wet filter cake was dissolved in ethyl acetate (500 mL) and washed with 200 mL of brine. The aqueous phase was slightly cloudy, so it was acidified with a small amount of hydrochloric acid and returned to the organic phase. The aqueous phase was separated, and the organic phase was dried over magnesium sulfate, filtered and ncentrated ip massio, obtaining a light yellow oil. This crude product was diluted with acetonitrile and chromatographed on a reversed-phase column with 415 g of C18, eluting with a mixture of 50-100% acetonitrile in water. The product was isolated in the form of cream-colored foam. The foam was dried in a vacuum at 45 "C for 48 hours, obtaining (145)-8-

13-(2-Idispiro|2.0.2.1|heptan-7-ylylethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!17 .3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 195) (3.32 g, 68 95 ). IN NMR (400 MHz, DMSO-ab) b 12.48 (5, 1H), 8.20 (y, U - 2.8 Hz, 1H), 7.81 (90.94 - 8.2 Hz, 1H), 7.57 (ai, 9 - 8.5, 7.2 Hz, 1H), 7.05 (a, 9 - 7.1 Gu, 1H), 6.97 (a, U - 8.5 Hz, 1H), 6.91 (a, U - 8.2 Hz, 1H), 6.71 (a, U - 68.5 Hz , 1H), 6.08 (y, 9 - 2.7 Hu, 1H), 4.21 (Id, U - 6.7, 1.3 Hu, 2H), 3.92 (y, U - 12.0 Hz, 1H), 3.16 (5, 1H), 2.95 (0, U - 13.3 Hz, 1H), 2.78 - 2.66 (t, 1H), 2.07 (5, 1H), 1.92 - 1.72 (t, 4H), 1.60 (5, 6H), 1.51 (5, ЗН), 1.47 (I, 9 - 6.5 Hz, 1H), 1.31 (d, y - 12.2 Hz, 1H), 0.89 - 0.77 (t, 4H), 0.69 - 0.61 (t, 2H), 0.53 - 0.45 (t, 2H) . MO-IER t/2 calc. 617.27844, found 618.4 (M-NT) zhk; retention time: 10.29 min. (Method RH B).

Salts Sadya, Maz and K- compound 195 were obtained by mixing compound 195 with Ca(OSNH)2, Masosn3) and KOH, respectively: mixing compound 195 (1 g) and Ca(OSNH2 (83 mg) in methanol (65 ml) at room temperature for 30 min and then at 65 °C for 30 min; mixing Compound 195 (0.6 g (1 mmol)) in Meon (40 mL) with 25 wt. 95 Ma(osnase) in Meon (250 mL ( 1 molar equivalent)) at 60 "C for 20 minutes; and mixing Compound 195 (0.6 g) in

From acetone (11 ml) with 1 n. KOH (1 molar equivalent) at 50 °C for 1 hour. After filtering the resulting hot solutions, the filtrates were evaporated to dryness to give the desired amorphous salts, respectively (LCCO data not shown).

Example 54: Preparation of 8-I3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2A6-thia-3, 9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 196) and 8-I3-(2-idispiro|2.0.2.1|)heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab6 -thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2 ,4-trione (enantiomer 2) (Compound 197) nie - boron nm Y Mom s te / - uva: zivr 1 0-5. NM ver2

In B- My in o sho) BC

Ge) uz ooo o o o o o o o o o o o o o o o o

Phase Mom for « Mom is about A 2 An as I SO Mn o A SO Mn va in epapioteg 1 in epapioteg 2

Stage 1: tert-butyl 4-(2-I((6-(2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carbonyl| sulfamoyl|-2-pyridylamino|ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate o o o 9,

Nom-87 salo to, Mom Mi si. t) o o o ni ni h /

Du enn SCHO lin me o she uk ny Bo. in (o) 2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxylic acid (412 mg, 1.145 mmol) and carbonyldiimidazole ( 185.7 mg, 1.145 mmol) were combined in anhydrous tetrahydrofuran (10.47 ml) and stirred for 60 min at 50 "C. Then a tetrahydrofuran solution (7 ml) of tert-butyl-2,2-dimethyl-4-(2 -((b-sulfamoyl-2-pyridyl)amino|ethoxy|pyrrolidine-1-carboxylate (431.5 mg, 1.041 mmol) and 1,8-diazabicyclo/5.4.F)undec-7-ene (400.7 mg , 393.6 μl, 2.632 mmol). The reaction was heated at 50 C for 4 h. The reaction was diluted with ethyl acetate and washed with 1 M aqueous citric acid followed by brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified on silica gel using a gradient from 100 90 hexanes to 75 95 ethyl acetate in hexane to give tert-butyl-4-(2-(6-C2-chloro-6-(3-(2)) as an off-white solid -dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3 -carbonyl|sulfamoyl|-2-pyridyl|amino|ethoxy)|-2,2-dimethylpyrrolidine-1-carboxylate (452 mg, 57 95). MO-IER ip/2 calc. 755.2868, found 756.41 (Ma1)x; Holding time: 0.92 min. (Method of RH A).

Stage 2: 8-I(3-(2-idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab-thia-3 ( Compound 188) o oo

N | ooo

Kri ana A - m/ b he v ni m. HC n A o-4 SMT yuY -Uy org 0 i

Tert-butyl 4-(2-C6-C2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|isosulfamoyl|-2- pyridylyamino|ethoxy|-2,2-dimethylpyrrolidine-i-carboxylate (410 mg, 0.5421 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (800 μL, 10.38 mmol) was added to the mixture.The reaction solution was stirred at room temperature 30 min.

The reaction solution was concentrated in vacuo to dryness under reduced pressure to give a residue.

This residue was combined with potassium carbonate (450 mg, 3.256 mmol), cesium fluoride (105 mg, 0.6912 mmol), 3 A molecular sieves, and dimethyl sulfoxide (5 mL) in a vial, purged with nitrogen, closed with a lid, and heated to 140 "C and stirred for 20 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by reversed-phase preparative chromatography (column C18, from 3095 to 9995 acetonitrile (without

From the modifier) in water (mM hydrochloric acid) for 30 minutes) to give a white solid, 8-I3-(2-(dispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl |-12,12-dimethyl-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10)hetracose-1(23),5(10),6, 8,19,21-hexane-2,2,4-trione (Compound 188) (330 mg, 97 90). IN NMR (400 MHz, DMSO-ab) b 12.55 (5, 1H), 8.19 (a, U - 2.8 Hz, 1H), 7.79 (a, U - 8.2 Hu, 1H), 7.59 (i, U - 7.9 Hz . , U - 6.6 Hz, 2H), 4.10 (5, 2H), 3.88 (I, U - 11.8 Hz, 1TN), 3.60 (a, U - 12.4 Gu, 1H), 2.86 (5, 1H), 2.07 ( , In - 11.9, 6.0

Hz, 1Н), 1.81 (d, y - 6.6 Hz, ЗН), 1.57 (y, 9 - 9.2 Hz, 6Н), 1.47 (I, 7 - 6.5 Hz, 1Н), 1.23 (5, 2Н), 0.94 - 0.75 (t, 4H), 0.64 (da, 9 - 8.4, 4.5 Hz, 2H), 0.50 (ad, 9 - 7.68, 4.3 Hz, 2H). MO-IER t/: calc. 619.2577, found 620.33 (M.-1)x; retention time: 2.25 min. (Method of RH B).

Stage 3: 8-I(3-(2-ydispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab-thia-3 ,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-

hexane-2,2,4-trione (enantiomer 1) (Compound 196) and 8-13-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12, 12-dimethyl-15-oxa-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10)htetracose-1(23),5(10),6,8, 19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 197) oo 7 9 cm". as Ame epapnotek 1 epapioteg 2

The racemic compound 8-3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2A6-thia-3,9, 11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 188) (320 mg, 0.5112 mmol) was subjected to chiral NKR chromatography. The following NCRK protocol was used: SpigaIRak A5-3 (150

X 21 mm), Z μm; Mobile phase 35 C: 30 95 acetonitrile: methanol (90:10), 70 Fo carbon dioxide.

The first eluted enantiomer was 8-I(3-(2-idispiro|2.0.2.1|)heptan-7-ylylethoxy)-1H-pyrazol-1-yl|I-12,12-dimethyl-15-oxa-2A6-thia -3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4 -trione (enantiomer 1) (Compound 196) (63 mg, 39 95). MO-IER t/2 calc. 619.2577, found 620.33 (Ma1)xk; Holding time: 2.18 min. (Method of RH B). The second eluted enantiomer was 8-(3-(2-idispiro|2.0.2.1|)heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-15-oxa-2Ab6-thia -3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4 -trione (enantiomer 2) (Compound 197) (62 mg, 39,965). IN NMR (400 MHz, DMOSO-ab) b 12.56 (5, 1H), 8.19 (a,

In 2.8 Hu, 1H), 7.79 (a, - 8.2 Hu, 1H), 7.59 (1, 9 - 7.8 Hz, 1H), 7.09 (a, y - 7.2 Hz, 1H), 6.93 (9, 9 - 8.2 Hz , 1H), 6.70 (a, U - 8.5 Hz, 1H), 6.08 (a, U - 2.8 Hz, 1H), 4.211.9 - 6.7 Hz, 2H), 3.88 (I, U - 11.9

Hu, 1H), 3.60 (y, U - 13.0 Hz, 1H), 3.17 (a, U - 4.3 Hu, ЗН), 2.86 (5, 1H), 2.08 (aa, U - 11.6, 5.9 Hz, 1H), 1.81 (d, U - 6.5 Hz, ZN), 1.57 (y, 9 - 9.4 Hz, 6H), 1.47 (1, 9 - 6.5 Gu, 1H), 1.42 - 1.33 (t, 1H), 1.24 (5, 1H ), 0.96 - 0.78 (t, 4H), 0.72 - 0.57 (t, 2H), 0.57 - 0.42 (t, 2H). MO-IER t/2 calc. 619.2577, found 620.33 (M.-1)khk; Holding time: 2.18 min. (Method of RH B).

Example 55: Preparation of 20,20-dimethyl-4-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3 ( Compound 206) and 20,20-dimethyl-4-73-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3, 9,14,22-pentaazatetra cyclo(/16.2.1.111,14.02,7 |docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) ( compound

From 207)

Fa naz her Sho B de a pai Y nav, Mo ob lev 0-7 shsh- b da VosM

VosM (0) o re) o o o o Zo she: id these o Am ce 6 (di t L-m that in id na tru matu epapioteg 1 epapioteg 2

Stage 1: tert-butyl 4-I(3-(3-((2-chloro-6-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|pyridin- 3-carbonyl|sulfamoyl|pyrazol-1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o o9o ooo Ku 85, ZYM id nom M | Z no o u U 6-0 MTM

M. - and 0-4 SMT oi fi and VosM Vosm

ZOH

2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (350 mg, 0.9620 mmol) and carbonyl diimidazole ( 188 mg, 1.159 mmol) were combined in tetrahydrofuran (8.0 mL) and stirred for 90 min at room temperature. Then tert-butyl-2,2-dimethyl-4-13-(3-sulfamoylpyrazol-1-yl) was added propyl|pyrrolidine-1-carboxylate (446 mg, 1.154 mmol) followed by anhydrous 1,8-diazabicyclo(5.4.0)undec-7-ene (360 μL, 2.407 mmol), and the reaction mixture was stirred at room temperature for 30 minutes followed by heating to 40 "C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by chromatography on silica gel using a gradient from 100 90 hexanes to 80 95 ethyl acetate in hexane and then on a second silica gel column using a gradient from 100 95 dichlorom ethane to 15 95 methanol in dichloromethane to obtain tert-butyl-4-I(3-(3-(2-chloro-6-I3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|pyrazole-1 -yl|pyridine-3-carbonyl|isosulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (360 mg, 51,905) as a white solid. MO-IER t/2 calc. 731.3232, found 732.5 (Ma1)f; retention time: 2.14 min. (Method RK 5).

Stage 2: 20,20-dimethyl-4-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ...

La so id o o o i m ke SHYH zi TM -7 NN "Zh n id no

Tert-butyl 4-I3-I3-C2-chloro-6-I(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy | pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|pyrazole -1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (360 mg, 0.4916 mmol), potassium carbonate (400 mg, 2.894 mmol), molecular sieves ZA and MMR (10 mL) were added to 20 -milliliter vial for a microwave oven, purged with nitrogen, closed with a lid, heated to 160 "C and stirred for 96 hours. The reaction vessel was cooled to room temperature, filtered and the filtrate was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution.

The organic layers were separated, dried over sodium sulfate, evaporated and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 90 95 ethyl acetate in hexane to give 20,20-dimethyl-4-13-(2-(2,2,3 ,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2(7),3 ,5,11(22),12-pentane-8,10,10-trione (compound 198) (59.7 mg, 20 95) as a white solid. 1H NMR (400 MHz, Spiogoitogite-4) b 8.42 (5, 1H), 8.17 (a, U - 2.8 Hz, 1H), 7.68 (y, 9 - 8.2 Hu, 1H), 7.48 (a, 9 - 2.3 Hz , 1H), 7.07 (a, U - 2.3 Hz, 1H), 7.03 (a, 9 - 8.3 Hz, 1H), 5.88 (9.9 - 2.7 Gu, 1H), 4.43 - 4.29 (t, 1H), 4.24 (I, 9 - 7.2 Hz, 2H), 4.00 - 3.87 (t, 1H), 2.75, 9 - 8.3 Hz, 1H), 2.16 - 2.12 (t, 1H), 2.03 - 1.94 (t, 2H), 1.76 ( d, U - 7.1 Hu, ZN), 1.57 (a, 9 - 15.2 Hu, 6H), 1.47 (I, U - 12.3 Hz, 2H), 1.10 - 1.05 (t, 6H), 0.97 (5, 6H), 0.91 - 0.75 (t, 2H), 0.25 (5 9 - 7.2 Hz, 1). MO-IER t/2 calc. 595.29407, found 596.2 (Ma1)k; Holding time: 1.94 min. (Method of RH E).

Stage 3: 20,20-dimethyl-4-(3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,14 22-pentaazatetracycloi16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 206) and 20,20-dimethyl-4-13-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,22 - pentaazatetracyclo/16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 207) ooo ooo ooo

In хи сМ7З хи сМ7З epapioteg 1 epapioteg 2

Racemic 20,20-dimethyl-4-13-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 22 -pentaazatetracycloi16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (compound 198) (45.4 mg, 0, 07544 mmol) was separated by chiral NCR chromatography using SpPigaIRak A5-H (column 250 x 21.2 mm, particle size 5 μm) with 32 95 acetonitrile:methanol (90:10; no modifier))/68 95 mobile phase of carbon dioxide at 0.5 ml/min, 20,20-dimethyl-4-13-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy|-1H-pyrazole-1-) was obtained as the first eluted enantiomer yl)-10X6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10 ,10-trione (enantiomer 1) (Compound 206) (18.9 mg, 84,965) as a white solid. MO-IER t/2 calc. 595.29407, found 596.2 (Ma1)f; Holding time: 1.94 min. (Method of RH E). The second eluted enantiomer was 20,20-dimethyl-4-[3-(2-(2,2,3,3-tetramethylcyclopropyl)ethoxy |-1H-pyrazol-1-yl]-10XA6-thia-1,3,9 ,14,22-pentaazatetracyclo|16.2.1.111,14.02,7 |docosa- 2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 207) (19.2 mg, 85 95) as a white solid. NMR (400 MHz, Spiogothogite-a) b 8.38 (5, 1H), 8.17 (a, 9 - 2.8 Hz, 1H), 7.68 (a, 7 - 8.3 Hz, 1H), 7.48 (a, U - 2.3 Hu, 1H), 7.12 - 6.99 (t, 2H), 5.88 (9, 9 - 2.7 Hu, 1H), 4.43 - 4.30 (t, 1H), 4.24, 9 - 7.2 Hz, 2H), 3.93 (Y, U - 12.1 Hz, 1H), 2.74 (1, U - 8.2 Hz, 1H), 2.17 - 2.11 (t, 1H), 2.04 - 1.96 (t, 2H), 1.76 (d, 9U - 7.2 Hz, ЗН), 1.59 (5, 6Н), 1.47 (I, У - 12.1 Hz, 2Н), 1.08 (5, 6Н), 0.97 (v, 6Н), 0.92 - 0.71 (t, 2H), 0.25 (I, U - 7.2 Hz, 1H). MO-IER t/2 calc. 595.29407, found 596.2 (M--1)f; Holding time: 1.94 min. (Method of RH E).

Example 56: Preparation of (145)-12,12-dimethyl-8-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-2A6-thia-3, 9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 208) he vivr 1 he in M vs vier2 A -mvos «er Z tu DIT one, in let the,

WITH

(c) (c) ; x Give it

A. ss Tue 9-7 and si I all sim so chi

B o o o o n, "Y viyure Mem M soi ho zivr 7

M. 2 - - 0o- Mini

A Me V ra da ZO

ЕЗС о оо ооо и м? th and m'8- th on ov 0-7 vivr m shi shk

With / in nm many - In Aa others

EZS TO EZS

Stage 1: 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol vla on shk U ov z o EzS

A three-neck round-bottom flask with a volume of 1 l was equipped with a mechanical stirrer, a cooling bath, a dropping funnel and a temperature sensor.)-Ket. Lithium aluminum hydride granules (6.3 g, 0.1665 mol) were loaded into the vessel under a nitrogen atmosphere. Then tetrahydrofuran (200 ml) was loaded into the vessel under a nitrogen atmosphere. The mixture was left to stir

Leave at room temperature for 0.5 h to allow the granules to dissolve. Then crushed ice in water was loaded into the cooling bath and the reaction temperature was lowered to 0 "C. A solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (20 g, 0.1281 mol) in tetrahydrofuran (60 mL), and a clear pale yellow solution was added dropwise over 1 hour. After the addition was complete, the mixture was allowed to warm slowly to room temperature and stirring was continued for 24 hours. The suspension was cooled to 0 °C using an ice bath and then quenched very slowly, dropwise, adding water (6.3 ml), then sodium hydroxide solution (15 wt. 95; 6.3 ml) and, finally, water (18.9 ml).

The reaction temperature of the resulting white suspension was 5 °C. The suspension was stirred at °C for 30 min, and then filtered through a layer of celite 20 mm thick. The precipitate on the filter was washed with tetrahydrofuran (2 x 100 ml). The filtrate was dried over sodium sulfate (150 g) and then filtered. The filtrate was concentrated under reduced pressure to obtain a clear colorless oil (15 g) containing a mixture of the product 3,3,3-trifluoro-2,2-dimethylpropan-1-ol in tetrahydrofuran (73 95 wt. product (10.95 g ) and 27 wt. 95 tetrahydrofuran, as determined by 1 H-

NMR). The distillate from the rotary evaporator was distilled at atmospheric pressure using

30-centimeter Midgeich column with 8.75 g of residue containing 60 wt. 95 tetrahydrofuran and 40 wt.95 product (3.5 g). These product mixtures in tetrahydrofuran were combined to give 3,3,3-trifluoro-2,2-dimethylpropan-i-ol (14.45 g, 61 wt.95 in tetrahydrofuran, yield 79 95). IN NMR (400 MHz, DMSO-ab) b 4.99 (I, U - 5.7 Hz, 1H), 3.38 (ai, U - 5.8, 0.9 Hz, 2H), 1.04 (a, U - 0.9 Hz, 6H).

Stage 2: tert-butyl 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate from 0-0 p uvos

EZS d- -080606- vn, -

EzS

A mixture of 3,3,3-trifluoro-2,2-dimethylpropan-y-ol (10 g, 70.36 mmol) and tert-butyl-3-hydroxypyrazole-1-carboxylate (12.96 g, 70.36 mmol) in toluene (130 mL) was treated with triphenylphosphine (20.30 g, 77.40 mmol), then isopropyl-M-isopropoxycarbonyliminocarbamate (14.99 mL, 77.40 mmol), and the mixture was stirred at 110 C for 16 h. The yellow solution was concentrated under reduced pressure, diluted with heptane (100 ml) and the precipitated triphenylphosphine oxide was removed by filtration and washed with a mixture of heptane/toluene 4:11 (100 ml). The yellow filtrate was evaporated and the residue was purified by chromatography on silica gel with a linear gradient of ethyl acetate in hexane (0-40 95) to give tert-butyl-3-(3,3,3-trifluoro-2,2-dimethyl-methyl-propoxy)pyrazole- 1-carboxylate (12.3 g, 57 U) as an off-white solid. 1H NMR (400 MHz, DMSO-ab) b 8.10 (a, U - 3.0 Hz, 1H), 6.15 (9.9 - 3.0 Hz, 1H), 4.18 (5, 2H), 1.55 (5, 9H), 1.21 (5, 6H). MO-IER t/2 calc. 308.13477, found 309.0 (M--1) k; retention time: 1.92 min. (Method of RH B).

Stage 3: 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole in le -- yam

Ezs Ezs

Tert-butyl-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazole-1-carboxylate (13.5 g, 43.79

2 mmol) was treated with 4 M hydrogen chloride in dioxane (54.75 mL, 219.0 mmol) and the mixture was stirred at 45 °C for 1 hour. The reaction mixture was evaporated to dryness and the residue was extracted with 1 M aqueous sodium hydroxide (100 mL) and methyl -tert-butyl ether (100 ml), washed with brine (50 ml) and extracted with methyl tert-butyl ether (50 ml).

The combined organic phases were dried over sodium sulfate, filtered and evaporated to obtain 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole (9.0 g, 96 95) as a crude white waxy solid. 1H NMR (400 MHz, DMSOO-ab) b 11.91 (5, 1H), 7.52 (0.9 - 2.2 Hz, 1H), 5.69 (Her, U - 2.3 Hu, 1H), 4.06 (5, 2H), 1.19 (5, 6H). MO-IER t/2 calc. 208.08235, found 209.0 (M--1) k; retention time: 1.22 min. (Method of RH B).

Stage 4: tert-butyl 2-chloro-6-I3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl|Ipyridin-

Z-carboxylate (in) oh de

M. and: (F) o---7 "MN and o

Z / - y uva 6066662 Ge) Am M (Fi

EZS bib tm sa Z kA

To a solution of tert-butyl-2,6-dichloropyridine-3-carboxylate (10.4 g, 41.9 mmol) and 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole ( 9.0 g, 41.93 mmol) in M,M-dimethylformamide (110 ml) was added potassium carbonate (7.53 g, 54.5 mmol) and 1,4-diazabicyclo|2.2.2)octane (706 mg, 6.29 mmol) and the mixture was stirred at room temperature for 16 h. The creamy suspension was cooled in a cold water bath and cold water (130 ml) was slowly added.

The thick suspension was stirred at room temperature for 1 h, filtered and washed with water to obtain tert-butyl-2-chloro-6-(3-(3,3,3-trifluoro-2,2-

dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxylate (17.6 g, 9995) as an off-white solid after vacuum drying. 1H NMR (400 MHz, DMSO-46) 5 8.44 (a, U - 2.9 Hz, 1H), 8.31 (a, - 8.4 Hu, 1H), 7.76 (a, 9 - 8.4 Hz, 1H), 6.26 (j, In - 2.9 Hz, 1H), 4.27 (5, 2H), 1.57 (5, 9H), 1.24 (5, 6H). MO-IER t/2 calc. 419.12234, found 420.0 (M--1)f; retention time: 2.36 min. (Method of RH B).

Stage 5: 2-chloro-6-I3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (c) АХ (6) - -- - t -I-I

Z Me Ul - M village

EzS EzS

Tert-butyl-2-chloro-6-I(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxylate (17.6 g, 40.25 mmol ) suspended in isopropanol (85 mL), treated with hydrochloric acid (34 mL 6 M, 201 mmol) and heated under reflux for 3 hours (almost completely dissolved under reflux and began to precipitate again). The suspension was diluted water (51 mL) under reflux and allowed to cool to room temperature with stirring for 2.5 h.The solid was collected by filtration, washed with 1:1 isopropanol/water (50 mL), additional water, and dried in an oven under vacuum at 45-50 "C with nitrogen purging overnight to obtain 2-chloro-6-I|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-Z- carboxylic acid (13.7 g, 9195) as an off-white solid. 1H NMR (400 MHz, DMOO-ab) b 13.61 (5, 1H), 8.44 (a, 9 - 2.9 Hz, 1H), 8.39 ( a, U - 8.4 Hz, 1H), 7.7 7 (a, y - 8.4 Hu, 1H), 6.25 (y, U - 2.9 Hu, 1H), 4.28 (5, 2H), 1.24 (5, 6H). MO-IER t/72 calc. 363.05975, found 364.0 (M'-1)f; Holding time: 1.79 min. (Method of RH B).

Stage 6: tert-butyl (45)-4-I3-((6-Ce-chloro-6-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine -3-carbonyl|Isulfamoyl|-2-pyridylIamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate 57 i Still /y sh-- 2-chloro-6-I3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl|pyridine-33-carboxylic acid (174.5 mg , 04702 mmol) and carbonyl diimidazole (95.31 mg, 0.5878 mmol) were combined in tetrahydrofuran (2.223 mL) and stirred for 90 min at room temperature. Then

tert-Butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (194 mg, 0.4702 mmol) was added as a solution in tetrahydrofuran (855 μL) followed by the addition of 1,8-diazabicyclo/5.4.0)undec-7-ene (357.9 mg, 2.351 mmol) and the reaction mixture was stirred at 50 "C for 2.5 hours. Stirring was continued at room temperature temperature for 4 days. The reaction mixture was then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and then with brine. The organic layers were separated, dried over sodium sulfate, evaporated, and then purified by silica gel chromatography using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate, yielding the pure product and fractions mixed with the acid of the starting material. The mixed fractions with the starting acid were combined, evaporated, and purified using a reversed-phase HPLC-MS method using a Hypa C18 column (2) (75 x 30 mm, size particles of 5 μm), sold by Rpepo tepeh (art.: 00С-4252-00 -АХ) and a double gradient from 30-99 956 mobile phase

In the course of 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 257023 fractions of pure product about was combined with pure material from the starting column with silicon dioxide to obtain tert-butyl (4 5)-4-I3-Cb6-Ce-chloro-6-I(3-(3,3,3-trifluoro-2,2- dimethylpropoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridyl|amino|propyl/|-2,2- dimethyl-pyrrolidine-1-carboxylate (110.4 mg, 31 95) in the form of white solid substance. MO-IER t/27 calcd. 757.2636, found 758.4 (M--1)k, retention time: 0.9 min. (Method RH A).

Stage 7: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridylI|sulfonyl|- 6-I3-(3,3,3- trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl|pyridine-3-carboxamide t 9 o or

N

- I'm back SHY I have I pam ШЯ shsh- MN dshch- MN

In a round-bottomed flask containing tert-butyl (45)-4-I3-C(6-Ce-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl |pyridine-3-carbonyl|sulfamoyl|-2-pyridyl|amino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (110.4 mg, 0.1456 mmol) was added dichloromethane (2 mL) and trifluoroacetic acid ( 450 μl, 5.841 mmol). After 1 h at room temperature, the reaction mixture was evaporated to dryness. The crude reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The product precipitated and a little methanol was used for extraction. The organic layer was separated and evaporated to give 2-chloro -M-I((6-I3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl/-6-(3-(3,3,3-trifluoro-2 ,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxamide (95 mg, 9995) as a white solid. MO-IER t/: calcd. 657.2112, found 658.4 (M--1) LCD; retention time: 1.62 min. (Method

RK B).

Stage 8: (145)-12,12-dimethyl-8-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-2Ab-thia-3,9 ,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 208 ) ti chu o oo - - M - NM many 7-37 U / - MN

EzS KL EzS

Cesium fluoride (33.5 mg, 0.2205 mmol), potassium carbonate (100 mg, 0.7236 mmol), 3 A molecular sieves, and a solution of 2-chloro-M-(6-I3-(35)) were added to the vial. -5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl/|-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridin- 3-carboxamide (95 mg, 0.1443 mmol) in dimethyl sulfoxide (2.5 mL). The reaction mixture was capped and placed in an oil bath preheated to 150 °C overnight. The reaction mixture was cooled to room temperature, filtered, and purified using HPLC (30 95- 99 95 acetonitrile: water with 0.1 96 modifier hydrochloric acid, obtaining (145)-12,12-dimethyl-8-I|3-(3,3,3-trifluoro-2,2-dimethylpropoxy )-1H-pyrazol-1-yl|-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9, 19(23),20-hexane-2,2,4-trione (compound 208) (45.5 mg, 51 95) as a reddish-brown solid. 1H NMR (400

MHz, DMSO-ab) b 12.49 (5, 1H), 8.23 (y, U - 2.68 Hz, 1H), 7.82 (a, 9 - 8.2 Hz, 1H), 7.58 (ai, U - 8.5,

Zo 7.2 Hz, 1H), 7.05 (a, U - 7.1 Hz, 1H), 6.95 (9, U - 8.2 Hz, 2H), 6.71 (a, U - 8.5 Hz, 1H), 6.18 (a, 9 - 2.7

Hz, 1H), 4.27 - 4.19 (t, 2H), 3.92 (y, U - 12.4 Hz, 1H), 3.16 (5, 1H), 2.95 (y, U - 13.5 Hz, 1H), 2.71 4.9 - 10.8 Hz, 1H), 2.13 (5, 1H), 1.86 (aa, 9 - 11.8, 5.2 Hz, 1H), 1.77 (5, 1H), 1.65 - 1.48 (t, 9H), 1.35 (ad, 9U - 25.8 , 14.3 Hz, 1H), 1.24 (5, 6H). MO-IER t/ calc. 621.2345, found 622.3 (MaA1) k; retention time: 2.24 min. (Method of RH B).

Example 57: Preparation of (145)-12,12-dimethyl-8-(3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl|-2A6-thia-3 ( Compound 212)

Зо8 о

K on ziver 1 E b 7 vier2 K --M vierZz

E ----- -x ---tt- 235 - ---- theaya-

ZK - zl (9) he on no m. Zh

E vier 4 se schi KKU vier 5 o o vier 6

Ов ко --ь-ь к - ----

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IS

KU

(c) Z

NM" and

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E s-g Osi i sim ts in AD o o o o o o m"? y y m" - 5

M I we, M I | n 1 o- M M Os zier9 r/d MK ek t r g)

Stage 1: (3,3,3-trifluoro-2,2-dimethyl-propyl)umethanesulfonate o. at

E 5 (Fin! l

Ki - 5 g

E E

IS

Triethylamine (45.0 mL, 322.9 mmol) was added to a solution of 3,3,3-trifluoro-2,2-dimethylpropan-i-ol (17 g, 104.1 mmol) in dry dichloromethane (150 mL). The reaction mixture was cooled to 0"C and methanesulfonyl chloride (10 mL, 129.2 mmol) was slowly added dropwise under a nitrogen atmosphere. The resulting heterogeneous mixture was stirred for 1 h while warming to ambient temperature. The reaction was then quenched with cold water (150 mL) and extracted with dichloromethane (200 ml) twice. The organic layer was dried over sodium sulfate, filtered and evaporated (bath temperature 20 "C at 300 mbar) to obtain 3,3,3-trifluoro-2,2-dimethylpropylmethanesulfonate (18.4 g, 8095) in the form of a transparent yellowish liquid. IN NMR (400 MHz, chloroform-9) 6 4.13 (d, y - 2.4 Hz, 2H), 3.03 (d, y - 2.4 Hz, ZN), 1.21 (d, y - 2.4 Gu, 6H).

Stage 2: 4, 4, 4-trifluoro-3,3-dimethyl-butanitrile (c) o. 7, -

ВЕ 5М

E (o) --)F141E dl and E

IS

Sodium cyano (20.05 g, 409.1 mmol) was added to a solution of (3,3,3-trifluoro-2,2-dimethylpropyl)umethanesulfonate (30.00 g, 136.2 mmol) in dimethyl sulfoxide (150 mL). The reaction mixture was equipped with a reflux condenser and heated at 120 "C for 3 days. Then the reaction mixture was cooled to 0 "C and ice water was added, followed by saline solution. Then the reaction mixture was extracted twice with ether, the organic layers were combined and dried over sodium sulfate, filtered and evaporated to obtain 4,4,4-trifluoro-3,3-dimethylbutanitrile (18.43 g, 90 95) as an orange liquid . IN NMR (400 MHz, chloroform-a) 6 2.56 (s, 2H), 1.33 (s, bH).

Stage 3: 4, 4, 4-trifluoro-3,3-dimethyl-butanoic acid

E - M On

Eh - in the hook - eh

IS

To a solution of 4,4,4-trifluoro-3,3-dimethylbutanitrile (12 g, 39.70 mmol) in ethanol (100 ml) was added sodium hydroxide (35 ml of 6 M, 210.0 mmol). The resulting clear amber solution was heated to 70"C overnight. The reaction mixture was cooled to ambient temperature, water (30 ml) was added to the reaction mixture and extracted with ether.

The ether layer was washed with 6 M sodium hydroxide. The aqueous layers were combined, and the aqueous solution was carefully adjusted to pH 1 with concentrated hydrochloric acid at 0 "C. Then the mixture was extracted with ether (3 x 100 ml). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated (bath temperature 20 "C at 300 mbar) to obtain 4,4,4-trifluoro-3,3-dimethylbutanoic acid (3.8 g, 28 95). "IN NMR (400 MHz, Spiogoitopt-a) b 2.48 (5, 2H), 1.27 - 1.26 (5, 6H).

Stage 4: 4,4,4-trifluoro-3,3-dimethyl-butan-1-ol one one

KE K

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E E

A solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid (3.8 g, 11.17 mmol) was added dropwise through a dropping funnel to a suspension of lithium aluminum hydride (438 mg, 11.24 mmol) in ether (30 mL) ) in ether (30 mL) at 0 "C under a nitrogen atmosphere. The resulting suspension was stirred at ambient temperature for 24 hours. The reaction mixture was cooled in an ice bath and sequentially quenched with water (450 μL, 24.98 mmol) (slowly), then sodium hydroxide (450 μL 6 M, 2.700 mmol), then water (1.35 mL, 74.94 mmol) to give a white granular suspension, which was further stirred with anhydrous magnesium sulfate for 30 min, then filtered through celite. The precipitate was washed with ether and the filtrate was concentrated (at 400 mbar and 20 "C in a water bath) to obtain 4,4,4-trifluoro-3,3-dimethyl-butan-1-ol (1.5 g, 86 95) as a colorless liquid . 1H NMR (400 MHz, chloroform-4) 5 3.77 (td, y) - 7.3, 0.8

Gu, 2H), 1.79 (t,9 - 7.4 Hz, 2H), 1.15 (d, U - 0.8 Hz, 6H).

Stage 5: tert-butyl 3-(4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazole-1-carboxylate

KK shk and o Mem o -8--- and what

What E

E E

A solution of 4,4,4-trifluoro-3,3-dimethyl-butan-yl-ol (1.0 g, 6.404 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (1.2 g, 6.515 mmol) , triphenylphosphine (1.9 g, 7.244 mmol) in dry tetrahydrofuran (10 mL) was cooled in an ice bath and SIAO (1.5 mL, 7.618 mmol) was slowly added under nitrogen. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, then with brine and dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified

Chromatography on a silica gel column using a gradient of 100% hexanes to 50% ethyl acetate in hexane afforded tert-butyl-3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazole-1-carboxylate ( 650 mg, 31 95) in the form of a colorless oil. IN NMR (400 MHz, Spiogoitogt-a) b 7.83 (a, U - 2.9 Hz, 1H), 5.84 (y, 9 - 3.1 Hz, 1H), 4.38, 9 - 7.2 Hz, 2H), 1.98, 9 - 7.1 Hz, 2H), 1.61 (5,

OH), 1.18 (5, 6Н). MO-IER t/ calc. 322.15042, found 323.18 (M--1)f; Holding time: 0.74 min. (Method of RH A).

Stage 6: 3-(4, 4, 4-trifluoro-3,3-dimethyl-butoxy)-1H-pyrazole (o; m. AH r o-(7 Mn o-7 M iv) A

M vo --x shchi

IS

IS

A solution of tert-butyl 3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazole-1-carboxylate (650 mg, 2.017 mmol) and trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (4 mL ) was stirred for 4 h at room temperature. Volatile substances were removed in vacuo, the residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated to give 3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazole (448 mg, 100 95) as a colorless oil. MS-IER t/7 calc. 222.09799, found 223.09 (M'-1) k; retention time: 0.53 min. (Method of RH A).

Stage 7: tert-butyl 2-chloro-6-(3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl|Ipyridin-

Z-carboxylate

(o) ok AY to I r

E I r E -

E (about M ke 5

IS

A mixture of 3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)-1H-pyrazole (448 mg, 2.016 mmol), tert-butyl 2,6-dichloropyridine-3-carboxylate (501 mg, 2.019 mmol) ), potassium carbonate (336 mg, 2.431 mmol) and 1,4-diazabicyclo(2.2.2|octane (46 mg, 0.4101 mmol) in dimethyl sulfoxide (5 mL) were stirred at room temperature for 15 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 100 90 hexanes to 20,956 ethyl acetate in hexane to afford tert-butyl-2- chloro-6-(3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazol-1-yl|pyridine-3-carboxylate (471 mg, 54 95) as a white solid. TN NMR (400 MHC,

SNiogoiogt-a) b 8.36 (y, y - 2.8 Hz, 1H), 8.19 (da, 9 - 8.2, 1.8 Hz, 1H), 7.69 (ai, U - 8.2, 1.8 Hz, 1H), 5.94 (a, U - 2.8 Hz, 1H), 4.38 (Her, U - 7.2 Hz, 2H), 2.03 (1, U - 7.2 Hz, 2H), 1.62 (0, U - 2.1 Hz, 9H), 1.22 (5, 6H). MO-IER Ip/2 calc. 433.138, found 434.2 (M--1)k; retention time: 0.91 min. (The method of RH

AND).

Stage 8: tert-butyl (45)-4-(3-I((6-(2-chloro-6-I3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazole-1- yl|Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

KO A AH II in -- Vosm MN

EzZS WITH KI

A solution of tert-butyl-2-chloro-6-(3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl|pyridine-3-carboxylate (150 mg, 0.3457 mmol) in trifluoroacetic acid (150 μL, 1.947 mmol) and dichloromethane (1 mL) were stirred at room temperature for 2 h. The solvent was removed and the residue was dried under high vacuum to give a white solid. To a solution of this solid in tetrahydrofuran (2 mL) was added carbonyldiimidazole (68 mg, 0.4194 mmol) and the reaction mixture was stirred for 4 hours at room temperature, then tert-butyl (45)-2,2-dimethyl-4-13-(b-sulfamoyl-2-pyridyl)amino| propyl|pyrrolidine-1-carboxylate (146 mg, 0.3539 mmol) in tetrahydrofuran (2 mL), then 1,8-diazabicyclo/5.4.O0)undec-7-ene (110 μL, 0.7356 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a mixture of saturated ammonium chloride and saline (1:1). The organic phases were separated, dried over

With sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100 95 dichloromethane to 2095 methanol/dichloromethane to give tert-butyl (45)-4-I3-C(6-C2-chloro-6-(3-(4, 4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl|pyridine-3-carbonyl|Isulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (82 mg , 31 95) in the form of a white solid. MO-IER t/2 calcd. 771.27924, found 772.36 (Ma-1)-, retention time: 0.89 min. (method RH A).

Stage 9: (145)-12,12-dimethyl-8-I3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl|-2Ab-thia-3,9 . ) 9 chu o o, r o-0n M si M. 2 o-K M M M. a

Solution of tert-butyl (45)-4-I3-C(6-C2-chloro-6-(3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl|pyridin- 3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (82 mg, 0.1062 mmol) in dichloromethane (500 μl) and trifluoroacetic acid (100 μl,

1.307 mmol) was stirred at room temperature for 4 hours. Then the solvents were removed and the residue was dried under vacuum. This residue was dissolved in dimethylsulfoxide (5 ml), oven-dried molecular sieves Z A were added, and the reaction mixture was stirred for 10 min.

Cesium fluoride (51 mg, 0.3357 mmol) and potassium carbonate (48 mg, 0.3473 mmol) were then added, and the reaction mixture was heated at 130 °C overnight. and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50-99 95 mobile phase B for 15.0 min (mobile phase A - water (0.0595 hydrochloric acid). Mobile phase B - acetonitrile) to give ( 145)-12,12-dimethyl-8-I3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl|-2Ab-thia-3,9,11,18, 23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 212) (34.5 mg, 51 95) as a white solid. 1H NMR (400

MHz, Spiogoitogit-a) b 9.84 (5, 1H), 8.20 (a, U - 2.68 Hu, 1H), 8.07 (a, U - 8.4 Hu, 1H), 7.54 (ai, U - 15.1, 7.2 Hz, 2H ), 7.27 (a, U - 8.3 Hz, 1H), 6.57 (d,9U - 8.1 Gu, 1H), 5.91 (a, U - 2.8 Hz, 1H), 4.3841.9 7.2

Hu, 2H), 3.91 (5, 1H), 3.41 - 3.31 (t, 1H), 3.17 (a, U - 14.5 Hu, 1H), 3.06 (I, U - 9.7 Hz, 1H), 2.62 (5, 1H ), 2.09 (aa, U - 12.3, 7.9 Hu, 1H), 2.03 (1, 9 - 7.2 Hu, 2H), 1.62 (9, U - 3.6 Hz, 11), 1.22 (a, U - 0.8

Hz, 6H). MO-IER t/2 calc. 635.2502, found 636.2 (M--1)x; Holding time: 1.14 min. (Way

RH U).

Example 58: Preparation of 8-I(3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 1) (Compound 209), 8 -13-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111, 14.05,10|hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 2) (Compound 210), 8-I3-(3, (3-Dimethylbutyl)-2-oxoimidazolidin-1-yl|- 12,12,17-trimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 1) (Compound 215), 8-

13-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111,14.05 ,10|hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 2) (Compound 216), 8-I3-( 3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10| hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (Compound 218) and 8-Y3-(3,3 -dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10|hetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (Compound 219) (e) (c) - zier 1 o uk zier2 mya - t ii li m, -- Z in (o) (c) 5-/ her A

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Stage 1: tert-butyl M-(2-(3,3-dimethylbutylamino)ethyl carbamate (o); pH b - - mninm

X /

To a solution of tert-butyl M-(2-aminoethyl)carbamate (25 g, 156.04 mmol) in methanol (400 mL) was added 3,3-dimethylbutanal (20 mL, 159.35 mmol). The mixture was stirred at room temperature for 1 hour. It was cooled to 0 "C and sodium borohydride (6.2 g, 163.88 mmol) was added in portions. The resulting mixture was stirred at room temperature for 16 hours.

The reaction mixture was concentrated, then the residue was re-dissolved in ethyl acetate (500 ml).

The obtained solution was washed twice with a saturated aqueous solution of sodium bicarbonate (2 x 300 ml) and saline solution (1 x 500 ml), then dried over sodium sulfate. The solution was filtered and concentrated to give tert-butyl-N-(2-(3,3-dimethylbutylamino)ethyl| carbamate (37.5 g, 96 95) as an oil. MO-IER t/27: 244.37, found 245.5 (M--1)k; retention time: 2.25 min. (Method

RH R).

Stage 2: 1-(3,3-dimethylbutyl)imidazolidinyl-2-one and) bet vi -

To tert-butyl M-(2-(3,3-dimethylbutylamino)ethylcarbamate (15.8 g, 64.65 mmol) was added tetrahydrofuran (200 mL) in a 1000 mL vial. Solid tert-butoxide (21.77 g, 194.0 mmol) of potassium and the resulting yellow solution was heated to 60°C for 3 hours. The mixture was cooled to ambient temperature and acidified to pH 1-2 with aqueous hydrochloric acid (1 M) and concentrated under reduced pressure. The aqueous residue was extracted ethyl acetate (2 x 200 ml), the organic phase was washed twice with saline solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a beige solid, which was purified by flash column chromatography on silica gel (from O bo to 10 90 methanol in ethyl acetate) gives 1-(3,3-dimethylbutyl)imidazolidinyl-2-one (8.3 g, 72 95) as a white solid. 1H NMR (300

MHz, DMOO-a6) ppt 0.89 (5, 9H), 1.26-1.37 (t, 2H), 2.97-3.09 (t, 2H), 3.14-3.22 (t, 2H), 3.24-3.32 (t, 2H), 6.12-6.32 (t, 1H). MO-IER tp/2 calc. 170.252, found 171.2 (M--1)w; retention time: 2.17 min. (The method of RH N).

Stage C: tert-butyl 4-I3-(6-(2,6-dichloropyridine-3-carbonyl)usulfamoyl|-2-

Zo pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

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2,6-dichloropyridine-3-carboxylic acid (220 mg, 1.146 mmol), carbonyldiimidazole (185 mg, 1.141 mmol), and anhydrous tetrahydrofuran (7 mL) were charged to a 100 mL round-bottom flask purged with nitrogen under a nitrogen atmosphere. The mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. In a separate 100 ml flask, a solution of tert-butyl-2,2-dimethyl-4-IIZ-(6b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (485 mg, 1.137 mmol) in anhydrous tetrahydrofuran ( With ml) was obtained in a nitrogen atmosphere and later it was added using a syringe to a solution of activated ester. 1,8-diazabicyclo/5.4.O01undec-7-ene (373 μL, 2.494 mmol) was added via syringe and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. The solvents were removed under reduced pressure and the resulting thick oil was treated with aqueous citric acid. The two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined organic extracts were washed with saline (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue was dissolved in dichloromethane and purified by chromatography on silica gel using a gradient of ethyl acetate (from 0 9Uo to 100905 over 30 minutes) in hexane to give tert-butyl 4-13-((6-K2,6-dichloropyridine-3 -carbonyl)usulfamoyl|-2-pyridylyamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (412 mg, 60 95) in the form of a solid foamy mixture of diastereomers of white color. MO-IER t/:2 calc. 599.1736 , found 600.21 (Ma) k, retention time: 0.77 min (Method RH A).

Stage 4: 8-chloro-12,12,17-trimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| I BE WITH

Solution of tert-butyl 4-I3-(6-(2,6-dichloropyridine-3-carbonyl)sulfamoyl|-2-pyridylyamino|butylI|-2,2-dimethyl-pyrrolidine-i-carboxylate (412 mg, 0.860 mmol) in dichloromethane (4 mL) and trifluoroacetic acid (0.55 mL, 7.187 mmol) was stirred at room temperature for 4 h. The solvents were removed and the residue was dissolved in ethyl acetate (100 mL). The solution was then washed with saturated sodium bicarbonate solution and water.

The organic extract was concentrated and dried under vacuum. The resulting residue was dissolved in dimethylsulfoxide (3 ml), molecular sieves Z A were added, and the reaction mixture was stirred

From within 10 min. Cesium fluoride (312.5 mg, 2.057 mmol) and potassium carbonate (288.4 mg, 2.087 mmol) were then added, and the reaction mixture was heated at 140 °C overnight. The reaction mixture was filtered and water was added to the filtrate. This solution was extracted with ethyl acetate. , and the organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated. 17-trimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20- hexane-2,2,4-rione (98 mg, 31,965). MO-IER t/72 calcd. 463.1445, found 464.19 (Ma-1)-4; retention time: 0.74 min. (Method of RH A).

Stage 5: 8-3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3 .1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 1) (Compound 209) and 8-I( I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-ylI|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05, 10) hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 2) (Compound 210)

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N emie i Z chn nyk h- o Zoo o Zrgotsa M i «m M a -- M ne -- h- ne diaz(egeoteg raig 1 diaz(egeoteg raig 2

8-Chloro-12,12,17-trimethyl-2Abthia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)htetracose-1(22) was loaded into a 4 ml vial ,5,7,9,19(23),20-hexane-2,2,4-trione (89 mg, 0.1918 mmol), 1-(3,3-dimethylbutyl)imidazolidinyl-2-one (46 mg , 0.2702 mmol), Rag(ara)z (46 mg, 0.05023 mmol), xanthophos (29 mg, 0.05012 mmol), cesium carbonate (314 mg, 0.9637 mmol) and anhydrous dioxane (3 mL ). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120"C for 14 hours. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and subjected to reversed-phase preparative HPLC (С18) using a gradient of acetonitrile in water (from 1 to 99 95 in 15 min) and hydrochloric acid as a modifier with obtaining as the first pair of eluted diastereomers, 8-IZ-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12, 17-trimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|)hetracose-1(22),5,7,9,19(23),20 -hexane-2,2,4-trione (pair of diastereomers 1) (Compound 209) (34 mg, 59 Or);

MO-IER t/2 distr. 597.30975, found 598.36 (M.-1); Retention time: 2.04 min (RCH B method); and as the second pair of eluted diastereomers 8-I(3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab6-thia-3,9,11,18, 23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 2) (Compound 210 ) (63.5 mg, quantitative); MO-IER t/72 calc. 597.30975, found 598.36 (M--1)-4; Retention time: 2.07 min (method RH B).

Stage 6: 8-3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3 .1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 1, enantiomer 1) (Compound 215) and 8 -I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloyl 1 7.3.1.111, 14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 1, enantiomer 2) (Compound 216)

IY Cho ooo ooo (e) va ie sa - m'8- sh o sa m/r aa ta a diaviegeoteg raig 1 diaz(egeoteg raig 1, epapboteg 1 diaziegeoteg raig 1, epapboteg 2 8-I3-(3,3- dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclol 1 7.3.1.111,14.05,10)hetracose-1( 22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 1) (Compound 209) (31 mg, 0.05134 mmol) was subjected to chiral NKR chromatography.

The following NCRK protocol was used: SpigaIRak A5-3 (150 X 2.1 mm), Z μm; Mobile phase 35"C: 3095 acetonitrile:methanol (90:10), 70 90 carbon dioxide. The first eluted enantiomer was 8-I(3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12, 12,17-trimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20 -hexane- 2,2,4-trione (pair of diastereomers 1, enantiomer 1) (Compound 215) (8.1 mg, 52 95). MO-IER t/27 calcd. 597.30975, found 598.1 (Ma1 )g; Retention time: 2.06 min. (Phase B). The second eluted enantiomer was 8-13-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl- 2A6-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10|)hetracose-1(22),5,7,9,19(23),20-hexane-2 ,2,4-trione (pair of diastereomers 1, enantiomer 2) (Compound 216) (9.1 mg, 58 90). IN NMR (400 MHz, DMSOO-ab) b 12.39 (5, 1H), 7.57 (y, U - 8.5 Hz, 1H), 7.38 (5, 1H), 7.10

- 6.82 (t, 2H), 6.68 (9, U - 30.7 Gu, 1H), 4.17 (5, 1H), 4.03 - 3.79 (t, 2H), 3.46 (r, U - 8.5, 7.9 Hz, 2H), 3.21 (yes, 9 - 10.3, 6.1 Hz, 2H), 3.00 (5, 2H), 2.10 (5, 1H), 1.79 (y, U - 10.2 Hz, 1H), 1.52 (y, - 50.3 Hz, 9H) .

MO-ER t/2 calc. 597.30975, found 598.2 (M--1); retention time: 2.06 min. (Method of RH B).

Stage t: 8-III-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3 .1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (Compound 218) and 8 -I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloyl 1 7.3.1.111, 14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (Compound 219)

J. Cho o do Y che o moi ie sya - wash "sha M 3. uva n TO and 9 uva n Go 3 uva n Go vd) M ne ulO M o t Z chi M na;

Chiaz'vgeoteg raig 2 diazeegeoteg raig 2, epapioteg 1 aiazegeoteg raig 2, epapioteg 2 8-I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia- 3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4- trione (pair of diastereomers 2) (Compound 210) (60 mg) was subjected to chiral NKR chromatography.

The following NKRK protocol was used: Rpepotepeh I 0X-4 AB5B-N (250 X 10 mm), 5 μm; mobile phase: 42 95 methanol (without modifier), 58 95 carbon dioxide; injection of 70 μl with a concentration of 24 mg/ml in methanol at a rate of 10 ml/min. The first eluted enantiomer was 8-13-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12,17-trimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo! 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (Compound 218) (9 mg, 30 95). IN NMR (400 MHz, DMSO-ab) 5 12.11 (5, 1H), 7.56 (I, U - 7.8 Hz, 1H), 7.51 - 7.31 (t, 2H), 7.15 (j, U - 7.3 Gu, 2H) . 2.25 (0, U - 21.1 Hz, 1H), 1.84 (aa, U - 11.9, 5.68 Gu, 1H), 1.71 (5, 1H), 1.57 (5, ЗН), 1.49 (5, 4H), 1.47 - 1.33 (t, ЗН), 1.29 - 1.17 (t, 7Н), 0.92 (5, 9Н). MO-IER t/2 calc. 597.30975, found 598.36 (Ma1)k; retention time: 0.82 min. (Method LC A) The second eluted enantiomer was 8-I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-ylI|-12,12,17-trimethyl-2Ab-thia-3,9,11,18, 23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (pair of diastereomers 2, enantiomer 2 ) (Compound 219) (14 mg, 46 95). MO-IER t/2 calc. 597.30975, found 598.33 (M'-1) k; retention time: 2.11 min. (Method of RH B).

From Example 59: Preparation of (145)-8-(3-(4,4-dimethylcyclohexyl)methyl|)|-2-oxoimidazolidin-1-yl).12,12-dimethyl-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo!17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 217) o zier 1 o zier2 7C i n. cho - 2 OBO" - nyah n ooo and i- Shov

NM, M- I'm glad to go x-

Stage 1: tert-butyl M-(2-(4,4-dimethylcyclohexyl)methylamino|ethylI|carbamat i) iv) 7 i on KK B-8-- Juice r Ж 5 n M c)

To a stirred solution of 4,4-dimethylcyclohexanecarbaldehyde (250 mg, 1.783 mmol) in anhydrous methanol (10 mL) was added a solution of tert-butyl-M-(2-aminoethyl)carbamate (286 mg, 1.785 mmol) and anhydrous methanol (1 mL) in a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 h, it was cooled to 0 °C (ice bath). Sodium borohydride (142 mg, 3.753 mmol) was then slowly added in two portions, the mixture was allowed to warm to ambient temperature, and stirring was continued. for 15 h. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2 x 15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butylN-(2-((4,4-dimethylcyclohexyl)methylamino|ethylcarbamate) (481 mg, 9595) as a yellow gum.

The crude substance was used in the next stage without additional purification. MO-IER t/2 calc. 284.24637, found 285.3 (M--1) k; retention time: 1.04 min. (Method of RH B).

Stage 2: 1-(4,4-dimethylcyclohexyl)methyl)| imidazolidinyl-2-one

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N ra ni ichrt OS

Solid potassium tert-butoxide (300 mg, 2.674 mmol) was added to a solution of tert-butyl M-(2-(4,4-dimethylcyclohexyl)methylamino|ethylcarbamate (240 mg, 0.8438 mmol) in anhydrous tetrahydrofuran (12 mL) in nitrogen atmosphere, and the reaction mixture was heated at 70 "C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature and acidified with hydrochloric acid (3.5 mL of 1.0 M, 3.500 mmol). Volatiles were removed under reduced pressure (not to dryness ). The aqueous residue was extracted with ethyl acetate (3 x 10 mL), and the organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient from 0 -10 96 methanol in dichloromethane for 30 minutes) to give 1-((4,4-dimethylcyclohexyl)methylimidazolidinyl-2-one (62 mg, 35 95) as an off-white solid. 1H NMR (400 MHz, Veplepe- ab) 5 5.42 (5, 1H), 3.10 (a,9 - 7.3 Hz, 2H), 2.64 - 2.77 (t, 2H), 2.77 - 2.71 (t, 2H), 1.58 - 1.52 (t, 2H), 1.46 - 1.42 (t, 2H), 1.38 (ad, U - 10.7, 3.5 Hz, 1H), 1.27 - 1.20 (t, 2H), 1.19 - 1.12 (t, 2H), 1.00 (5, ZN), 0.92 (5, ZN). MO-IER t/72 calc. 210.17322, found 211.2 (M--1) k; retention time: 1.17 min. (Method of RH B).

Stage C: (145)-8-(3-(4,4-dimethylcyclohexyl)methyl)|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18, 23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 217) o o,e o o0 ,o z zkh m, nk-y s m, X I new «m - || nom -Shnk pak MN sim wady goi x--

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione, (50 mg, 0.1111 mmol), 1-(4,4-dimethylcyclohexyl)methyl imidazolidinyl-2-one (26 mg, 0.1236 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bisidiphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) (Xanphos), and anhydrous dioxane ( 1.5 ml) in the specified order. Nitrogen was blown through the heterogeneous mixture for 2 min. Tris(dibenzylideneacetone)dipalladium (0) (10 mg, 0.01092 mmol) was then added under a nitrogen atmosphere and the mixture was purged with nitrogen for another 2 min, and the vessel was capped under a nitrogen atmosphere. The mixture was stirred at 115 °C overnight. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (60 μL, 1.055 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through 0.45 μm PTFE syringe disc filter UUpaytap The sample was purified using a preparative reversed-phase HPLC-MS (column I ipa C18 (2) (75 x 30 mm, particle size 5 μm) sold by Rpepotepeh (art.: 00C -4252-00-АЧ), a double gradient run of 30-99 95 acetonitrile in water for 15 min (hydrochloric acid as a modifier)). Fractions of the desired product were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 mL) and washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (145)-8-13-(4,4-dimethylcyclohexyl)methyl|-2-oxoimidazolidin-1-yl )-12,12-dimethyl-2Ab6-thia-3,9, 11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 217) (7.5 mg, 11 95) as a light yellow solid. 1H NMR (400

MHz, Meipapo!1-a«) b 7.70 (a, 9 - 8.6 Hz, 1H), 7.52 (aa, U - 8.5, 7.2 Gu, 1H), 7.43 (y, U - 8.6 Hz, 1H), 7.15 ( aa, 9 - 7.2, 0.8 Hz, 1H), 6.65 (aa, U - 8.5, 0.8 Gu, 1H), 4.10 - 4.07 (t, 1H), 4.07 - 4.02 (t, 1H), 4.02 - 3.95 (t, 1H), 3.56 - 3.52 (t, 1H), 3.51 - 3.47 (t, 1H), 3.23 (aa, U - 10.2, 6.7 Hz, 1H), 3.18 -

3.09 (t, 2H), 3.07 - 2.98 (t, 1H), 2.86 (I, U - 10.4 Hz, 1H), 2.21 - 2.07 (t, 1H), 1.83 (a9, U - 11.7, 5.4

Hu, 2H), 1.64 (5, ЗН), 1.63 - 1.55 (t, 5Н), 1.55 (5, ЗН), 1.48 - 1.35 (t, ЗН), 1.31 - 1.27 (t, 2Н), 1.22 - 1.16 ( t, ЗН), 0.91 (5, 6Н). MO-IER t/: calc. 623.3254, found 624.4 (Ma-1)k; retention time: 2.13 min. (Method of RH B).

Example 60: Preparation of 12,12-dimethyl-8-(3-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (Compound 220) n on o points in all seasons 1 in. lu vier2 (o)

Her in ve Mn Y uoFa vyvr Z M. ee zisr4 - om toi u-n She t po shk? 7 ooo 8 chn her - shi a ke ot o- MOM and M 3 in still But е-K o u e)

Stage 1: tert-butyl 3-(2-isopropyl-3-methyl-butoxy)pyrazole-1-carboxylate (c) o

N r on M (F) - t-shirt Ou So -

A solution of 2-isopropyl-3-methylbutan-1-ol (500 mg, 3.839 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (705 mg, 3.828 mmol), and triphenylphosphine (1.16 g, 4.423 mmol) in of dry tetrahydrofuran (20 mL) was cooled in an ice bath and OIAO (830 μL, 4.216 mmol) was slowly added under nitrogen. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, saline, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 0-50 95 ethyl acetate in hexane to obtain tert-butyl-3-(2-isopropyl-3-methylbutoxy)pyrazole-1-carboxylate (980 mg, 86 95) as a clear oil. YAN NMR (400 MHz,

SNiogoiogt-a) b 7.82 (y, y - 3.0 Gu, 1H), 5.84 (a, Y - 2.9 Hz, 1H), 4.29 (y, Y - 4.8 Hz, 2H), 1.91 (ra, Y - 6.9, 5.6 Hz, 2H), 1.61 (5, 9H), 1.44 - 1.24 (t, 1H), 0.98 (a, U - 6.8 Hz, 6H), 0.92 (a, U - 6.9 Hz, 6H).

MO-ER t/2 calc. 296.21, found 297.21 (Ma-1)k; Holding time: 0.84 min. (Method of RH A).

Stage 2: 3-(2-isopropyl-3-methyl-butoxy)-1H-pyrazole to M

M - still -X - - t of kn - o -

Tert-butyl-3-(2-isopropyl-3-methylbutoxy)pyrazole-1-carboxylate (980 mg, 3.306 mmol), dichloromethane (10 mL) and methyl alcohol (10 mL) were placed in a 250 mL round-bottom flask. Hydrogen chloride in 1,4-dioxane (4.1 ml of 4

M, 16.40 mmol). The homogeneous solution was stirred at 45 "C for 19 hours. Two additional equivalents of 4 M hydrogen chloride in 1,4-dioxane were added and stirred for another hour. Volatile

The substance was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and washed with aqueous 1N. sodium hydroxide. The layers were separated and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and the solvents evaporated to give 3-(2-isopropyl-3-methylbutoxy)-1H-pyrazole (490 mg, 76 95) as a colorless oil. MO-IER t/7 calc. 196.15756, found 197.1 (М-а1)ж; Holding time: 0.72 min. (Method of RH A).

Stage 3: Ethyl 2-chloro-6-N3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl|pyridine-3-carboxylate

(in)

M Y Z z 0-2 "MN y o M - s |. because it is Me -Y

Ethyl 2,6-dichloropyridine-3-carboxylate (547 mg, 2.486 mmol), 3-(2-isopropyl-3-methylbutoxy)-1H-pyrazole (488 mg, 2.486 mmol) and potassium carbonate (412 mg, 2.981 mmol) combined in anhydrous dimethylsulfoxide (b ml). 1,4-diazabicyclo(2.2.2|octane (56 mg, 0.4992 mmol)) was added and the mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (80 mL) and stirred for 15 min.

The resulting white solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated to give ethyl 2-chloro-6-N3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carboxylate (900 mg, 95 95). IN NMR (400 MHz, DMSO-ab) b 8.42 (a, U - 2.9 Hz, 1H), 8.39 (y, 9 - 8.5 Hz, 1H), 7.76 (a, U - 8.4 Hz, 1H), 6.20 (y , U - 2.9 Hz, 1H), 4.34 (d, U - 7.1 Hz, 2H), 4.26 (a, U - 4.8

Hu, 2H), 2.02 - 1.76 (t, 2H), 1.45 - 1.29 (t, 4H), 0.98 (a, U - 6.8 Hz, 6H), 0.92 (a, U - 6.68 Hu, 6H).

MO-ER t/2 calc. 379.16626, found 380.21 (M--1) k; retention time: 2.56 min. (Method of RH B).

Stage 4: 2-Chloro-6-N3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl|pyridine-3-carboxylic acid

Gee! i) uva y; from the district of ZM s - ke

Ethyl 2-chloro-6-I3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carboxylate (900 mg, 2.369 mmol), tetrahydrofuran (b ml) and aqueous sodium hydroxide were added to a round-bottomed flask. (1.4 ml of 5 M, 7,000 mmol). The reaction solution was allowed to stir for 4 hours at room temperature. The reaction solution was diluted with ethyl acetate (100 mL) and aqueous hydrochloric acid (12 mL, 1 M, 12.00 mmol) was added. The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give 2-chloro-6-N3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (655 mg, 79 95), which was used without additional purification. MO-IER tp/7 calc. 351.13498, found 352.19 (M--1)k; retention time: 0.87 min. (Method of RH A).

Stage 5: tert-butyl 5-I3-((6-(2-chloro-6-(3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl|Ipyridin-

Z-carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate ву оо9до

Nm sala o ke Mom | We are A 0-7 o-t M c o -ii Zm - (c) 2-chloro-6-I3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (170 mg,

Co) 0.4832 mmol) and carbonyldiimidazole (81 mg, 0.4995 mmol) were combined in anhydrous tetrahydrofuran (4 ml) and stirred for 75 min at 40 "C. Then a tetrahydrofuran solution (7 ml) tert-butyl-2 ,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (165 MG, 0.400 mmol) and 1,8-diazabicyclo/5.4.F)undec-7- en (152 μl, 1.016 mmol). The reaction was heated at 50 "C for 4 h. The reaction was diluted with ethyl acetate and washed with 1 M aqueous solution of citric acid, followed by washing with saline solution. The organic layer was dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 75 95 ethyl acetate in hexane to give tert-butyl /5-I(3- ((6-Ce-chloro-6-(3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine- 1-carboxylate (200 mg, 67 95). MO-IER t/2 calcd. 745.3388, found 746.3 (M--1)x, retention time: 0.87 min (RC Method K).

Stage 6: 12,12-dimethyl-8-13-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)y-2A6-thia-3,9,11 ... -femm te di mW that MN m ZHK n A -- - I -- 0-th "MM M M v a I le o) ze

Tert-butyl 5-IZ-K(6-Ce-chloro-6-(3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carbonyl|isosulfamoyl|-2-pyridylyamino|Ipropyl| -2,2-Dimethylpyrrolidine-i-carboxylate (200 mg, 0.2680 mmol) was dissolved in dichloromethane (3.5 mL) and hydrochloric acid (4 mL of 4 M in dioxane, 16.00 mmol) was added to the mixture. at room temperature for 2 hours.

The reaction mixture was concentrated to dryness under reduced pressure to obtain a precipitate.

This residue was combined with potassium carbonate (223 mg, 1.614 mmol), cesium fluoride (66 mg, 0.4345 mmol), Z A molecular sieves, and dimethyl sulfoxide (3.2 mL) in a nitrogen-purged, capped, heated vial. to 140 "C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered, and then purified by reverse-phase preparative chromatography (C18 column, 3095 to 9995 acetonitrile (without modifier) in water (5 mM hydrochloric acid) for 30 minutes) with a gradient to obtain 12,12-dimethyl-8-(3-I(3-methyl-2-(propan-2-yl/ubutoxy)-1H-pyrazol-1-yl-2Ab) as a white solid -thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5 (10),6,68,19,21-hexane-2,2 ,4-trione (compound 220) (65 mg, 3995). MO-IER t/2 calcd. 609.30975, found 610.47 (Ma1)k; retention time: 2.52 min (RC Method B).

Example 61: Preparation of (185)-20,20-dimethyl-4-(3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl|-10A6-thia-1 ,3,9,14 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (Compound 221)

Gee) what

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9-0 We ss and motor,

CT - oh I Hmm

Ua o o, -50 / ex 7 9-0 M ts (in vier2 M of U shchi - -8-- dia a at M

E o and de uU-m E --9 th

Zo Stage 1: tert-butyl (45)-4-(3-3-Ce-chloro-6-(3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl) Ipyridine-3-carbonyl|Isulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

(o) o 52o b oo

NOM" 8 uva nn sha: id is o- Mb 7 MO s- ok zl FENY cm -K 9 -k (in

E z-m E uU-m --9 --

Tert-butyl 2-chloro-6-(3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazol-1-yl|pyridine-3-carboxylate (150 mg, 0.3457 mmol) in a solution of trifluoroacetic acid (150 μL, 1.947 mmol) in dichloromethane (400 μL) was stirred at room temperature for 2 h. The solvent was removed and the residue was dried in vacuo. This material was dissolved in tetrahydrofuran (2 mL) and carbonyldiimidazole (69 mg, 0.4255 mmol) was added ), the reaction mixture was stirred for 4 hours at room temperature. Then tert-butyl (45)-2,2-dimethyl-4-|3-(3-sulfamoylpyrazol-1-yl)propyl|Ipyrrolidine-1-carboxylate (136 MG, 0.3519 mmol) in tetrahydrofuran (2 mL), followed by 1,8-diazabicyclo([5.4.0]undec-7-ene (110 μL, 0.7356 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture diluted with ethyl acetate and washed with a mixture of saturated ammonium chloride/saline solution (1:11). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by chromatograph on silica gel using a small gradient from 100 95 dichloromethane to 20 95 methanol/dichloromethane to give tert-butyl (45)-4-I3-I3-C2-chloro-6-(3-(4,4,4-trifluoro -3,3-dimethylbutoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (82 mg, 32 95) as a white solid substances MO-IER t/2 calc. 745.2636, found 746.14 (M--1)zhk; retention time: 0.87 min. (Method of RH A).

Stage 2: (185)-20,20-dimethyl-4-13-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3 ,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,71 docosa-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 221) (0,

From oo

And from B: le

M

5-4 Shchi 7 Kk and -- --a M - and Ka;

E (c) and dsch-

University of E. M. E

Solution of tert-butyl (45)-4-I3-I3-C2-chloro-6-(3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl|pyridin-3- carbonyl|sulfamoyl|pyrazol-1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (82 mg, 0.1099 mmol) in dichloromethane (400 μl) and trifluoroacetic acid (100 μl, 1.307 mmol) were stirred at room temperature temperature for 2 h. After the completion of the reaction, the solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (2 mL), the organic layer was collected, and the solvent was evaporated.

The obtained residue was dissolved in dimethylsulfoxide (5 ml), molecular sieves ZA and

The reaction mixture was stirred for 10 min. Cesium fluoride (54 mg, 0.3555 mmol) and potassium carbonate (48 mg, 0.3473 mmol) were then added, and the reaction mixture was heated at 130 °C overnight. ), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient run of 50 99 95 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile ) to obtain (185)-20,20-dimethyl-4-|3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl|-10Ab-thia-1,3 ,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 221) (14.3 mg , 21 95) in the form of a white solid. 1H NMR (400 MHz, Spiogoitogite-4) b 8.40 (5, 1H), 8.18 (a, U - 2.8 Hz, 1H), 7.68 (y, 9 - 8.2 Gu, 1H ), 7.48 (a, 9 - 2.3 Hz, 1H), 7.07 (a, 9 - 2.3 Hu, 1H), 7.02 (a, U - 8.3 Hu, 1H), 5.87 (a, 9 - 2.7 Hu, 1H), 4.36 (d, y - 7.0 Hz, ZN), 3.94 (i, U - 12.0 Gu, 1H), 214 (,9- 8.2 Hz, 1H), 2.14 (5, 2H), 2.02 (Y, 9 - 7.2 Hz, ZN), 1.76 (ai, U - 11.8, 5.2 Hz, 1H), 1.59 (5,

BN), 1.55 (5, ZN), 1.47 (Her, 9 - 12.1 Hz, 1H), 1.24 - 1.21 (t, 6H), 0.90 - 0.73 (t, 1H). MO-IER t/2 calc. 609.2345, found 610.07 (M--1)k; Holding time: 2.17 min. (Method of RH B).

Example 62: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutyl)imidazolidinyl-1-yl|-2A6b-thia-3 ( Compound 223)

E Ge) 5ier 1 E is n o F 5ier 1 bod - PO i let Rodu"

N

Oh oh

A Y M chad

MN | N M M - shchi i si ME m mn m M M M Mn ' od ha

EE J

Ge

Stage 1: tert-butyl M-(2-(4,4,4-trifluoro-3,3-dimethyl-butyl)amino|ethyl|carbamate

E (c) E iy tsu o r bod y Ou i Rodu"

N

Dess-Martin periodate (660 mg, 1.556 mmol) was added to a stirred solution of 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (210 mg, 1.345 mmol) in anhydrous methylene chloride (7 mL) at 0 "C (ice bath) under a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (60 mL) and saturated aqueous sodium bicarbonate (20 mL) was slowly added ( evolution of carbon dioxide gas was observed). Sodium thiosulfate (10 mL) was then added and stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2 x 20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and partially concentrated under reduced pressure (approximately to a volume of 2 ml) to obtain the intermediate aldehyde in the form of a crude solution.

Then, to a stirred solution of tert-butyl-(2-aminoethyl)carbamate (216 mg, 1.348 mmol) in anhydrous methanol (7 mL) was added the previously obtained ether solution of the intermediate aldehyde in anhydrous methanol (1 mL) under a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 h, it was cooled to 0" (ice bath). Sodium borohydride (110 mg, 2.908 mmol) was then slowly added in two portions, the mixture was allowed to warm to ambient temperature, and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 15 mL) and brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure with obtaining tert-butyl M-(2-K4,4,4-trifluoro-3,3-dimethyl-butyl)amino|ethyl carbamate (380 mg, 95 95) in the form of a transparent viscous oil. MO-IER t/2 calcd 298.1868, found 299.2 (M--1) k, retention time: 0.82 min (Method RH B).

Stage 2: 1-(4,4 4-trifluoro-3,3-dimethyl-butyl)imidazolidinyl-2-one o;

E (v; re ku Kai ---3»- sa en o wl chi

N E

EE

Solid potassium tert-butoxide (440 mg, 3.921 mmol) was added to a stirred solution of tert-butyl-N-(2-K(4,4,4-trifluoro-3,3-dimethyl-butyl)amino|ethyl Iicarbamate (380 mg , 1.274 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogen, and the reaction mixture was heated at 70 C for 13 h. The heterogeneous mixture was allowed to cool to ambient temperature and acidified with aqueous hydrochloric acid (5.0 mL, 1.0 M, 5,000 mmol), and the volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10 95 methanol in dichloromethane gradient over 30 minutes) to give 1-(4,4,4-trifluoro-3,3-dimethyl-butyl)imidazolidinyl-2-one (172 mg, 60 95 ) in the form of an off-white solid. IN NMR (400 MHz, Veplepe-ab) b 5.50 (5, 1Н), 3.23 - 312 (t, 2Н), 2.71 - 2.66 (t, 2H), 2.65 - 2.59 (t, 2H), 1.64 - 1.53 (t, 2H), 1.01 (5, 6H). 196 NMR

(376 MHz, methanol-a4) b -79.87. MO-IER t/7 calc. 224.11365, found 225.1 (Ma-1)k; retention time: 1.08 min. (Method of RH B).

Stage 3: (145)-12,12-dimethyl-8-(2-oxo-3-(4,4 4-trifluoro-3,3-dimethylbutyl)imidazolidinyl-1-yl|-2A6-thia-3,9 ,11,18,23-pentaazatetracyclo| 1 7.3.1.111,14.05,10)|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 223) o ooo o Y B / he M/x raw iooo,

MN | N M uroshchi tsi 2 m mn m M M M Mn; od vl ha

E E

There is

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1 was added to a 4 ml bottle (23),5,7,9,19,21-hexane-2,2,4-trione (51 mg, 0.1133 mmol), 1-(4,4,4-trifluoro-3,3-dimethyl- butyl)imidazolidinyl-2-one (31 mg, 0.1383 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bisidiphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) and anhydrous dioxane (1.5 mL) in this sequence. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Tris(benzylideneacetone)dipalladium(0) (10 mg, 0.01092 mmol) was then added under nitrogen and nitrogen bubbled for another 2 min, and the reaction was quenched under nitrogen. The mixture was stirred at 115 "C during the night.

The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μL, 0.8792 mmol). Volatiles were removed under reduced pressure, and the residue was dissolved in dimethylsulfoxide (1.2 mL), filtered through a 0.45 µm PTFE syringe disc filter. The sample was purified using a preparative reversed-phase HPLC (Hipa C18 (2) column (75 x 30 mm, particle size 5 μm), which is sold

Rpepotepeh (art.: 00С-4252-00-АЧ), double gradient run of 30-99 95 acetonitrile in water for 15 min (hydrochloric acid as a modifier)). Fractions of the desired product were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (145)-12,12-dimethyl-8-(h-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutyl) Imidazolidinyl-1-yl|-2A6-thia-3,9,11,18,23-pentaazatetracycloyl-17.3.1.111,14.05,10)tetracose-1(22),5,7,9,19(23) ,20-hexaene-2,2,4-trione (compound 223) (37 mg, 51 95) as a yellowish solid. 1H NMR (400 MHz, MeishShapo!- a4) 6 7.70 (a, 9 - 68.6 Hz, 1H), 7.52 (da, U - 8.5, 7.2 Gu, 1H), 7.44 (a, 9 - 8.6 Hz, 1H), 7.15 (ai, y - 7.2, 0.8 Hz, 1H), 6.65 (da, 9 - 8.5, 0.8 Hz, 1H), 4.10 - 4.07 (t, 1H), 4.07 - 4.01 (t, 1H), 4.01 - 3.95 ( t

Zo 1H), 3.58 - 3.46 (t, 2H), 3.42 - 3.34 (t, 2H), 3.23 (I, U - 8.6 Gu, 1H), 3.08 - 2.97 (t, 1H), 2.854141, - 10.4 Hz, 1H ), 2.22 - 2.07 (t, 1H), 1.89 - 1.73 (t, 4H), 1.71 - 1.64 (t, 1H), 1.63 (5, ЗН), 1.62 - 1.55 (t, 2Н), 1.54 (5, ЗН ), 1.47 - 1.35 (t, 1H), 1.19 (5, 6H). MO-IER t/: calc. 637.2658, found 638.5 (MA) k; retention time: 1.9 min. (Method of RH B).

Example 63: Preparation of (145)-8-III-fluoro-5-(2-methylpropoxy)phenyl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111 ,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 224) (o) and AlaAMX - note OT Y M in June 8

SI M SI

IS

(o) 9 m dv hu ni zer Z on m- z

Ho - I'm MN

M SI

(at)

Uk -i-ya

E o oo, O ooo / M/ m same zivr4 sx m same

Ho and What and What (9) and (9) and

M SI Mn M M MN (9)

Wow

E --9 E

Stage 1: tert-butyl 2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (o) (9) | Uh v ra XX, -

Uh o 1 same M SI -

SI M SI

IS

5 Tert-butyl 2,6-dichloropyridine-3-carboxylate (15.0 g, 60.5 mmol) and (3-fluoro-5-isobutoxyphenyl)/boronic acid (13.46 g, 63.48 mmol) v/v were combined and completely dissolved in ethanol (150 ml) and toluene (150 ml). A suspension of sodium carbonate (19.23 g, 181.4 mmol) in water (30 mL) was added. Tetrakis(triphenylphosphine)palladium(0) (2.096 g, 1.814 mmol) was added under nitrogen. The reaction mixture was left under stirring at 60 "C for 16 h. Volatile substances were removed under reduced pressure. The remaining solids were partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with saline solution (1 x 100 ml ), dried over sodium sulfate, filtered and concentrated under reduced pressure.

The material was subjected to column chromatography on silica gel (from 0 95 to 20 95 ethyl acetate in a hexane gradient). The material was repurified by silica gel chromatography (isocratic 10095 hexane for 10 minutes, then a gradient from 0 to 5905 ethyl acetate in hexane) to give tert-butyl-2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylate (18.87 g, 49.68 mmol, 82 95), obtained as a colorless oil. YAN NMR (400 MHz, DMSO-4a6) 5 8.24 (a, - 8.0 Hz, 1H), 8.16 (a, - 8.1 Hu, 1H), 7.48 (ad, U - 9.4, 2.0 Hz, 2H), 6.99 (4 , U - 10.8, 2.2 Hz, 1H), 3.86 (y, U - 6.5 Hz, 2H), 2.05 (y, U - 13.3, 6.6 Hz, 1H), 1.57 (a, U - 9.3 Hz, 9H), 1.00 (i, y - 5.5

Hz, 6H). MO-IER t/2 calc. 379.13504, found 380.2 (M'a-1)k; retention time: 2.57 min. (Method of RH B).

Stage 2: 2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylic acid (6)

M: (c)

M: he at 5 o'clock

M SI (9) - - - - -t M SI

IS

IS

Tert-butyl 2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxylate (18.57 g, 48.89 mmol) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (60 mL, 780 mmol) was added and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was stirred at 40 "C for 2 h. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (100 ml). This solution was washed with a saturated aqueous solution of sodium bicarbonate (1 x 100 ml) and brine (1 x 100 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was suspended in ethyl acetate (75 mL) and washed with aqueous hydrochloric acid (1N, 1 x 75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure The obtained solid (17.7 g) was stirred as a suspension in dichloromethane (35 ml) at 40 "C for 30 minutes. After cooling to room temperature, the suspension was filtered and then washed with cold dichloromethane to give 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylic acid (11.35 g, 35.06 mmol, 72 95) in in the form of a white solid. TN NMR (400 MHz, DMSO-46) 5 13.76 (5, 1H), 8.31 (a, U - 8.0 Hz, 1H), 8.17 (0.9. - 8.1 Hz, 1H), 7.54 - 7.47 (t, 2H ), 7.00 (а, У - 10.8, 2.3 Hz, 1Н), 3.67 (а, У - 6.5 Hz, 2Н), 2.05 (y, 9 - 13.3, 6.6 Hz, 1Н), 1.01 (а, 9 - 6.7 Hz , 6H). MO-IER t/ calc. 323.1, found 324.1 (MAT) same; Holding time: 1.96 min. (Method of RH B).

Stage C: tert-butyl (45)-4-I3-C6-(2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carbonyl|Isulfamoyl|-2-pyridyl amino|propyl| -2,2-dimethyl-pyrrolidine-1-carboxylate o o o o o so B, 5 2-3

M N M-

XX, | tya on MN Am M si pl

Ge) - J 5 o

Ms. M

IS

In a 20 mL scintillation tube, 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylic acid (156 mg, 0.3751 mmol) and carbonyldiimidazole (61 mg, 0.3762 mmol) were mixed in tetrahydrofuran (2 ml) and stirred at room temperature for 2 hours. Then tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (100 mg, 0.2424 mmol) in tetrahydrofuran (2 ml), then /1,8-diazabicyclo/5.4.O0)undec-7-ene (110 μl, 0.7356 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 171 saturated aqueous ammonium chloride/brine solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 10095 ethyl acetate to give tert-butyl (45)-4-IZ3-C(6-C2-chloro-6-(3-fluoro-5-isobutoxyphenyl) pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (116 mg, 67 95). MO-IER t/72 calcd. 717.2763, found 718.38 ( M-1)h; time

From maintenance: 0.95 min. (Method of RH A).

Stage 4: (145)-8-13-fluoro-5-(2-methylpropoxy)/phenyl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 224) o oo 9 o// che shk 7 I; n - M-

Am M SI " Mn A M M MN (in) and ut Y

Solution of tert-butyl (45)-4-I3-C6-(2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carbonyl|isulfamoyl|-2-pyridylyamino|Ipropyl|-2, 2-Dimethyl-pyrrolidine-1-carboxylate (110 mg, 0.1531 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (200 μL, 2.614 mmol) was stirred at room temperature for 4 h. Then the solvents were evaporated.

The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was evaporated and dried in vacuum. The obtained residue was dissolved in dimethylsulfoxide (5 ml), molecular sieves Z A were added, and the reaction mixture was stirred for 10 min. Cesium fluoride (76 mg, 0.5003 mmol) and potassium carbonate (64 mg, 0.4631 mmol) were then added, and the reaction mixture was heated at 150 °C for 16 hours. , and the filtrate was purified by the method

Reversed-phase HPLC-MS using a double-gradient run of 20 80 95 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to give (145)- 8-13-fluoro-5-(2-methylpropoxy)enyl|-12,12-dimethyl-2Ab-thia-

3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 224) (12.5 mg, 14 95) as an off-white solid. 1H NMR (400

MHz, Spiogotogit-a) b 10.39 (5, 1H), 8.08 (a, U - 8.1 Hz, 1H), 7.60 - 7.46 (t, 2H), 7.36 (i, U - 1.9 Hz, 1H), 7.33 - 7.21 (t, 2H), 6.68 (1, U - 10.4, 2.3 Gu, 1H), 6.57 (da, U - 7.6, 1.4 Hz, 1H), 4.75 (5, 1H), 3.90 (5,1H), 3.77 ( a, U - 6.6 Hz, 2H), 3.36 (I, y) - 8.7 Hz, 1H), 3.17 (a, U - 12.6 Gu, 1H), 3.08 (I, U - 9.6

Hz, 1H), 2.69 (a, U -10.1 Hz, 1H), 2.12 (j, 9 - 13.3, 6.7 Hz, 2H), 1.68 (9, U - 2.6 Hz, 6H), 1.65 - 1.54 (t, 5H ), 1.04 (a, y -6.7 Hu, 6Н). MO-IER t/2 calc. 581.2472, found 582.34 (Ma); Holding time: 1.24 min. (Method RK 5).

Example 64: Preparation of (185)-4-3-fluoro-5-(2-methylpropoxy)phenyl|-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111, 14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (o) o i nat U eh on M 5ier 1

XX, | AND WHAT (about)

We are ik

Uk 3

IS

(c) (6)

OM o o, 5

M/ eh M 7 7 t XX, r and floor

But A Vod

M SI Mu 5ier 1

M -- I 0

E and and in u

Stage 1: tert-butyl (45)-4-I3-I3-C2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl|- 2,2-dimethyl-pyrrolidine-1-carboxylate of them 7 oo c) 9 μM 7 | and 5 on M XX. 2 I

M SI - --- -

To c)

ME

E uh u c)

In a 20 mL scintillation tube, 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylic acid (71 mg, 0.1707 mmol) and carbonyldiimidazole (27 mg, 0.1665 mmol) were mixed in tetrahydrofuran (2 ml) and stirred for b hours at room temperature. Then tert-butyl (45)-2,2-dimethyl-4-I3-(3-sulfamoylpyrazol-1-yl)/propyl|pyrrolidine-1-carboxylate (50 mg, 0.1294 mmol) in tetrahydrofuran (2 mL) was added ), and then 1,8-diazabicyclo/5.4.Oundec-7-ene (42 μl, 0.2809 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:11 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated.

The resulting brown residue was purified by silica gel chromatography using a slight gradient from 100 96 dichloromethane to 20 95 methanol/dichloromethane to give tert-butyl (45)-4-I3-I3-(2-chloro-6-(3-fluoro-5 -isobutoxyphenyl)pyridine-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (52 mg, 58 95) as a white solid. MO-IER t/2 calcd. 691.2607, found 692.0 (Ma-1)w; Chas

From retention: 0.92 min. (Method of RH A).

Stage 2: (185)-4-3-fluoro-5-(2-methylpropoxy)phenyl|-20,20-dimethyl-10X6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02 ,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione

oh oh

M/ (in) Fr

Uh YOU (and M

Same Ж" У У " in m Ho - She in)

IS

In E

(in)

Solution of tert-butyl (45)-4-I3-I3-C2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carbonyl|isosulfamoyl|pyrazol-1-yl|Ipropyl|-2, 2-Dimethyl-pyrrolidine-1-carboxylate (52 mg, 0.07512 mmol) in dichloromethane (500 μL) and trifluoroacetic acid (100 μL, 1.307 mmol) was stirred at room temperature for 4 h. Then the solvents were evaporated.

The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was removed and dried under high vacuum, obtaining a residue that was dissolved in dimethylsulfoxide (5 ml), molecular sieves 3 A were added and the reaction mixture was stirred for 10 min. Cesium fluoride (38 mg, 0.2502 mmol) and potassium carbonate (34 mg, 0.2460 mmol) were then added, and the reaction mixture was heated at 150 °C for 16 hours. , and the filtrate was purified by reversed-phase HPLC-MS using a double gradient run of 50 - 99 95 mobile phase B for 15.0 min (mobile phase A - water (0.05595 hydrochloric acid), mobile phase B - acetonitrile) with obtaining (185)-4-III-fluoro-5-(2-methylpropoxy)phenyl|-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (14.0 mg, 34 95) off-white solid. 1H NMR (400 MHz, Spiogothogite-a) b 7.65 (y, U - 7.9 Hz, 1H), 7.47 (a, 9 - 2.3 Gu, 1H), 7.35 - 7.32 (t, 1H), 7.28 - 7.23 (t, 1H), 7.08 (5, 1H), 6.95 (a, U - 7.9 Gu, 1H), 6.64 (y, 9 - 10.4, 2.3 Hz, 1H), 4.33 (y, U - 13.3 Hz, 1H), 3.92 (ad, U - 13.9, 11.2 Hz, 1H ), 3.75 (9, 9 - 6.6 Hz, 2H), 2.75 (5, 1H), 2.21 - 2.07 (t, ZH), 1.98 (ad, U - 19.3, 10.6 Hz, 1H), 1.80 - 1.72 (t, 1H), 1.63 (5, ЗН), 1.61 (5, ЗН), 1.48 (i, У - 12.2 Gu, 1H), 1.38 - 1.21 (t , 1H), 1.03 (5, ЗН), 1.02 (5, ЗН), 0.93 - 0.70 (t, 2Н). MO-IER t/2 calc. 555.23157, found 556.14 (M--1)k; retention time: 1.09 min. (Method RK 7).

Example 65: Preparation of (145)-12,12-dimethyl-8-13-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)-2Ab-thia-3 ( Compound 227) c)

M c) c)

Y shcha m ss y and V y We

I uk M si vVos M I. "ier1 u 4 s write - - tro (9) (9) (9) (9)

SM SHE hu M | y: xx /;? x n Mo zier Z | IN

M. - -- the city of M

Stage 1: tert-butyl /(4S)-4-III-Cb-(2-chloro-6-I3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl |-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (c) (c) x/Y o o

Y r: SM so and M 7 and | I

Hm 4 s and VosM Mo sh- s Seya 5-0. MN 8- pK 5-5. what

Coo)

From a 50 mL flask charged with carbonyldiimidazole (76 mg, 0.4687 mmol) and 2-chloro-6-(3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (164 mg, 0.4661 mmol),

nitrogen was pumped off and refilled with nitrogen (3X). Tetrahydrofuran (5 mL) was added, and the mixture was stirred at 50 C for 1 hour. Then a solution of tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (160 mg, 0.3878 mmol) and 1, 8-diazabicyclo(|5.4.FOundec-7-ene (150 mg, 0.9853 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at 50 °C overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sulfate of sodium, the mass was evaporated and purified by reverse-phase preparative HPLC ((С18): 1-99 95 acetonitrile in water/hydrochloric acid modifier (15 min)) to obtain tert-butyl (45)-4-I3-(6-( 2-chloro-6-(3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carbonyl|!sulfamoyl|-2-pyridylyamino|propyl/|-2,2- dimethylpyrrolidine-1- carboxylate (90 mg, 31 95). MO-IER t/2 calcd 745.3388, found 746.47 (MA) k, retention time: 1.96 min (RC Method B).

Stage 2: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridylI|sulfonyl|- 6-I3-(2-isopropyl-3- methyl-butoxy)pyrazol-1-yl|pyridine-3-carboxamide (hydrogen chloride salt) o 9 (c) Kf 4 h , 5 5 M zy AJ 73

M | - --y - - o u m si 5-47 M si and less MN nm

Solution of tert-butyl (45)-4-I3-C6-Ce-chloro-6-I3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino| propyl|-2,2-dimethylpyrrolidine-1-carboxylate (90 mg, 0.12 mmol) in dioxane (5 mL) was treated with 6 M hydrochloric acid in dioxane (1.3 mL, 7.800 mmol) and stirred at room temperature for C hours

The mixture was evaporated in mass, obtaining 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl/|-6-(3-(2 -isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridine-3-carboxamide (hydrochloride salt) (100 mg, 38 95). MO-IER t/: calcd 645.2864, found 646.36 (MA) k; retention time: 0.27 min (RC Method A).

Stage 3: (145)-12,12-dimethyl-8-(3-13-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)-2Ab-thia-3, 9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 227) o 9 th (9) MA and s r» zi tm boju i m - -Kya - 5 --k. about in M. M

MN to O nm her

In a 5 mL vial, potassium carbonate (102 mg, 0.7380 mmol), cesium fluoride (45 mg, 0.2962 mmol), and 4A molecular sieves (300 mg) were sealed and purged with nitrogen. A solution of 2-chloro-M -I((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-6-(3-

Zo (2-isopropyl 3-methylbutoxy)pyrazol-1-yl|pyridin-3-carboxamide (hydrochloride salt) (100 mg, 0.1465 mmol) in dimethyl sulfoxide (2 mL) and the mixture was stirred at 150 °C overnight.

The mixture was filtered and purified by reverse-phase preparative HPLC ((С18): 50-99 95 acetonitrile in water/hydrochloric acid modifier (15 min)) to obtain (145)-12,12-dimethyl-8-13-13-methyl- 2-(Propan-2-yl)butoxy|-1H-pyrazol-1-yl)y-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)htetracose -1(23),5(10),6,8,19,21-hexane-2,2,4-trione (compound 227) (18.0 mg, 20 95). IN NMR (400 MHz, Spiogothogite-a) b 9.99 (5, 1H), 8.19 (a, y - 2.68 Hz, 1H), 8.07 (a, y - 8.4 Hz, 1H), 7.60 - 7.48 (t, 2H) , 7.30 (a, U - 68.4 Hz, 1H), 6.61 - 6.52 (t, 1H), 5.91 (a, U - 2.8 Hz, 1H), 4.6-4.9 (bBg. 5, 1H), 4.28 (a, U - 4.9 Hz, 2H), 3.89 (5, 1H), 3.35 (aa, U - 9.9, 7.6 Hu, 1H), 3.17 (aa, U - 10.7, 6.7 Hz, 1H), 3.06 (Her, 7 - 9.7 Hz . U - 5.2 Hu, 1H), 1.01 (a, U - 6.9 Hu, 6H), 0.96 (a, U - 6.9 Hz, 6H). MO-IER t/: calc. 609.30975, found 610.39 (М--1)хж; Holding time: 1.59 min. (The method of RH U).

Example 66: Preparation of (145)-8-13-(2-(adamantan-1-yl)ethyl|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11, 18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 228)

about |)

Fr Fo u un Fu u ---yuk NA NM o -- "А A A -- MI Ge) - y I--zh h o, p M o Ii M azh y M

Ххх YOU hear "vra o | M -

МН - 0ЙЗ--

Stage 1: 2-(1-adamantyl)acetaldehyde on -o --

Solid Dess-Martin periodate (825 mg, 1.945 mmol) was added to a stirred solution of 2-(1-adamantyl)ethanol (300 mg, 1.664 mmol) in anhydrous dichloromethane (10 mL) at 0 °C (ice-water bath) in nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (60 mL) and saturated aqueous sodium bicarbonate (20 mL) was slowly added (to reduce the evolution of carbon dioxide gas ). Sodium thiosulfate (10 mL) was then added and stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(1-adamantyl)acetaldehyde (149 mg, 50 95) as a colorless semisolid.It was used in the next step without further drying or cleaning. 1N

NMR (400 MHz, benzene-ab) b 9.70 (t, U - 3.1 Hz, 1H), 1.95-1.93 (m, 1H), 1.89-1.87 (m, 2H ), 1.85 (d, 94 - 3.1 Hz, 2H), 1.68 (d, U - 3.0 Hz, ZN), 1.59 (dk, U 4.0, 2.0 Hz, 2H), 1.56 (d, U 2.2 Hz, 1H), 1.49 (d, U - 2.8 Hz, 6H).

Stage 2: tert-butyl M-(2-(2-(1-adamantyl)ethylamine|ethylcarbamate (c) and

T- and H suk S - 2

To a stirred solution of 2-(1-adamantyl)acetaldehyde (130.0 mg, 0.7292 mmol) in anhydrous methylene chloride (10 mL) was added a solution of tert-butyl-N-(2-aminoethyl)carbamate (117 mg, 0.7303 mmol) in anhydrous methylene chloride (1 mL) followed by the addition of glacial acetic acid (50 μL, 0.8792 mmol) at ambient temperature under a nitrogen atmosphere. The cloudy reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (242 mg, 1.142 mmol) was added in one portion at ambient temperature and stirring was continued overnight (13 hours). Volatile substances were removed under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed

With a saturated aqueous solution of sodium bicarbonate (2 x 15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl-M-(2-(2-(1-adamantyl) )ethylaminoethyl carbamate (209 mg, 89 95) in the form of a yellow resinous substance. The crude substance was used in the next step without additional purification. MO-IER t/2 calc. 322.26202, found 323.4 (M.-1); retention time : 1.19 min (Method RH B).

Stage 3: 1-(2-(1-adamantyl)ethylimidazolidinyl-2-one (o; o M sh--K -- - - M Lee

Ku hee

Solid potassium tert-butoxide (212 mg, 1.889 mmol) was added to a stirred solution of tert-butyl-N-(2-(2-(1-adamantyl)ethylamine|ethylcarbamate (200 mg, 0.6202 mmol)) in anhydrous tetrahydrofuran (12 mL) under a nitrogen atmosphere, and the reaction mixture was heated at 70 °C for 13 h. The heterogeneous mixture was allowed to cool to ambient temperature, acidified with aqueous hydrochloric acid (3.0 mL, 1.0 M, 3000 mmol), and the volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 x 10 ml), and the combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0- 10 95 methanol in a dichloromethane gradient over 30 min) to afford 1-(2-(1-adamantyl)ethylimidazolidinyl-2-one (53 mg, 34 95) as an off-white solid. IN NMR (400 MHz, Vepgepe- ab) b 4.92 (5, 1H), 3.35 - 3.25 (t, 2H), 2.85 - 2.76 (t, 2H), 2.74 - 2. 66 (t, 2H), 1.99 (p, U - 3.0 Hz, ЗН), 1.80 - 1.73 (t, ЗН), 1.69 (dd, у - 12.3, 2.3 Hz,

ЗН), 1.55 (а, У - 2.8 Hz, 6Н), 1.32 - 1.21 (t, 2Н). MO-IER tp/:2 calc. 248.18886, found 249.3 (MA) k; retention time: 1.67 min. (Method of RH B).

Stage 4: (145)-8-(3-(2-(adamantan-1-yl)ethyl|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 228) o bu o 9, /9 r / x (in) M / xx their | and her M-

Oh, wow

M MN | N M M M M M Mn sT- hi si M drill T-- hi ut

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose was added to a vial with a volume of 4 ml. 1(23),5,7,9,19,21-hexane-2,2,4-trione (20 mg, 0.04298 mmol), 1-(2-(1-adamantyl)ethylimidazolidinyl-2-one ( 13 mg, 0.05234 mmol), cesium carbonate (52 mg, 0.1596 mmol), 4,5-bisidiphenylphosphino)-9,9-dimethylxanthene (4 mg, 0.006913 mmol), and anhydrous dioxane (1.0 mL ) in the specified order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.004368 mmol) was then added under nitrogen and nitrogen bubbled for another 2 min, and the reaction was closed under nitrogen. The mixture was stirred at 115 "C during the night. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethylsulfoxide (1.0 mL) and filtered through a disc filter

From the UMpaitap syringe with PTFE 0.45 μm. The sample was purified using a preparative reversed-phase HPLC-MS (column Ipa C18 (2) (75 X 30 mm, particle size 5 μm), which is sold

Rpepotepeh (art.: 00С-4252-00-АЧ), (run with a double gradient of 30-99 95 acetonitrile in water for 15 min (hydrochloric acid as a modifier)| with obtaining (145)-8-13-(2- (adamantan-1-yl)ethyl|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracyclo!17.3.1.111,14.05,10 )hetracose-1 (22),5,7,9,19 (23),20-hexane-2,2,4-trione (compound 228) (13.0 mg, 44 95) as a yellowish solid. TN NMR (400 MHz, DMSO-ab) b 12.29 (5, 1H), 7.59 (y, U - 8.6 Hz, 1H), 7.57 - 7.53 (t, 1H), 7.41 (a, 9 - 8.5 Hz, 1H) . t, 2H), 3.26 - 3.16 (t, 2H), 3.13 - 3.03 (t, 1H), 2.93 (y, 9U - 13.3 Hz, 1H), 2.73 - 2.64 (t, 1H), 2.18 - 2.01 (t, 2H), 1.93 (5, ЗН), 1.80 (y, 9 - 12.1, 5.6 Hz, 2Н), 1.71 - 1.59 (t, 7Н), 1.58 (5, ЗН), 1.55 - 1.53 (t, 1Н), 1.51 (mo 5, 6H), 1.46 (5, ZN), 1.31 - 1.22 (t, ZN). MSO-IER t/2 calc. 661.341, found 662.5 (M.-1)k; retention time: 1.92 min. (Method of RH C).

Example 67: Preparation of (145)-8-3-(adamantan-1-yl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 230) n . yar OV ro: zuer2 chn, Y ro (9) - NS o 9 o 9 y Mukh

M hu M o eh K Her Z zier Z I | and m--

ХК , | yiv mnosha X, ME M Mn

MG si MU vod hi schu

Stage 1: tert-butyl M-(2-(1-adamantylamino)ethyl carbamate

M. lo - oi Viy vih - « -A- zhk a sok

MN, c) N Viy (c) - Her

To a stirred solution of tert-butyl-M-(2-oxoethyl)carbamate (505 mg, 3.172 mmol) in anhydrous methylene chloride (20 mL) was added solid adamantane-1-amine (hydrochloride salt) (475 mg, 3.141 mmol), followed by triethylamine (500 μl, 3.587 mmol) and glacial acetic acid (200 μl, 3.517 mmol) in the indicated order and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere. The heterogeneous (white suspension) reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (1.0 g, 4.718 mmol) was added in one portion at ambient temperature and stirring was continued overnight. Volatile substances were removed under reduced pressure. The residue was placed in ethyl acetate (30 ml) and washed with a saturated aqueous solution of sodium bicarbonate (2 x 15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl-M-( 2-(1- adamantylamino)ethylcarbamate (731 mg, 79 95) in the form of a yellow resinous substance. The crude substance was used in the next step without further purification. MO-IER t/2 calc. 294.23074, found 295.4 (Ma- 1) k, holding time: 0.91 min (Method RH B).

Stage 2: 1-(1-adamantyl)imidazolidinyl-2-one

N. M. O. Kh

Solid potassium tert-butoxide (465 mg, 4.144 mmol) was added to a stirred solution of tert-butyl /N-(2-(1-adamantylamino)ethylcarbamate (400 mg, 1.359 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogen, and the reaction mixture was heated at 70 "C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature and acidified with aqueous hydrochloric acid (5.5 mL, 1.0 M, 5.500 mmol) to pH 4-5, and the volatiles were removed at under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10 95 methanol in a dichloromethane gradient over 30 min) to give 1-(1-adamantyl)imidazolidinyl-2-one (69 mg, 23 95) as an off-white solid

From substance. 1H NMR (400 MHz, Veplepe-46) b 4.91 (5, 1H), 2.90 (ad, U - 8.5, 6.7 Hz, 2H), 2.64 (daa, y - 8.5, 6.7, 1.2 Hz, 2H), 2.21 ( y, U - 2.9 Hz, 6H), 2.06 (ai, 9 - 5.9, 3.0 Hz, ZN), 1.75 - 1.68 (t, ZN), 1.67 - 1.60 (t, ZN). MO-IER t/2 calc. 220.15756, found 221.2 (M.-1) housing; retention time: 1.36 min. (Method of RH B).

Stage C: (145)-8-(33-(adamantan-1-yl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 230)

o 9 o 9 /th M uh

M y: M movement about | y m- (9) xx M ХК - хы . F -- and »

MG si Mi give hi schu

(145)-8-chloro-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1 was added to a 4 ml vial (23),5,7,9,19,21-hexane-2,2,4-trione (20 mg, 0.04298 mmol), 1-(1-adamantyl)imidazolidinyl-2-one (13 mg, 0 .05901 mmol ), cesium carbonate (52 mg, 0.1596 mmol), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (4 mg, 0.006913 mmol), and anhydrous dioxane (1.0 mL) in the specified order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.004368 mmol) was then added under nitrogen, nitrogen was bubbled for another 2 minutes, and the vessel was sealed under nitrogen. The mixture was stirred at 115 °C overnight. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). The volatiles were removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1.0 mL), filtered through a disc filter of a 0.45 μm UUpaintap syringe

PTFE. The sample was purified using a preparative reversed-phase HPLC-MS HI column

Hypa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art.: 00С-4252-00-

АХ), (running with a double gradient of 30-99 95 acetonitrile in water for 15 min (hydrochloric acid as a modifier))) with obtaining (145)-8-I(IZ-«(adamantan-1-yl)-2- oxoiimidazolidin-1-yl|- 12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9, 19(23),20-hexane-2,2,4-trione (compound 230) (9 mg, 33 9o) as a yellowish solid NMR (400 MHz, DMSOO-ab) b 12.28 (5, 1H) , 7.61 - 7.57 (t, 1H), 7.57 - 7.52 (t, 1H), 7.38 (a, U - 8.6 Hz, 1H), 7.03 (a, 9 - 7.1 Hz, 1H), 6.96 (a, U - 7.3 Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 3.96 - 3.74 (t, ЗН), 3.53 - 3.46 (t, 2H), 3.12 - 3.03 (t, 1H), 2.93 (y, U - 13.4 Hz, 1H), 2.73 - 2.65 (t, 1H), 2.2 - 2.02 (t, 8H), 1.83 - 1.71 (t, 2H), 1.65 (5, 5H), 1.62 - 1.59 (t, 1H), 1.57 (5, ZN), 1.55 - 1.48 (t,

ZN), 1.46 (5, ZN), 1.36 - 1.22 (t, ZN). MO-IER t/2 calc. 633.30975, found 634.5 (M--1) t; retention time: 1.66 min. (Method RK 5).

Example 68: Preparation of (145)-8-(3-(3,3-dicyclobutylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23 -pentaazatetracycloi|17.3.1.111,14.05,10|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 231) one

I zier Z on zier 1 "M ovvr2 M 7 zier 4 about HER --- - X d ----хk (9) k X x M (c)

І 8-7 o o - decision o k y- -- y t 54 nia IF results on 5-0 Msi 5-0 kisi M 5th and 7th M - m

From o-k,

o euao Y oh go and M Uh m? xx

Ш) 5ier 11 | n 5-47 MU in -OIOOOI2Y- I in a -y d- and what MN

TRA

M

N

Stage 1: 2,2-di(cyclobutyl)ethyl methanesulfonate (c) 0-8

AND

(in)

To a 100 mL round-bottom flask containing 2,2-di(cyclobutyl)ethanol (1.0 g, 6.483 mmol) in dichloromethane (11.0 mL) was added triethylamine (2.72 mL, 19.51 mmol). The reaction mixture was cooled to 0 °C in an ice bath. Methanesulfonyl chloride (891 mg, 7.118 mmol) was added dropwise (exothermic, a weak yellowish suspension was formed) and the reaction mixture was stirred for 1 h while warming to room temperature. After stirring for 1 h, the reaction was then quenched cold water (15 mL) (the mixture turned into a clear pale yellow solution) and extracted twice with dichloromethane (20 mL), the organic layer was washed with brine, the organic layer was dried over sodium sulfate, filtered, and evaporated to give crude 2,2-di( cyclobutyl)ethylmethanesulfonate (1.5 g, 100 95) as a clear colorless to pale yellow liquid. This product was used in the next reaction without further purification. 1H NMR (400 MHz, chloroform-4) b 4.03 (d, 9 - 4.6

Hu, 2H), 2.97 (s, ЗН), 2.37-2.12 (m, 2H), 2.09-1.47 (m, 1Z3H).

Stage 2: 3,3-di(cyclobutyl)propanenitrile its otr --t tt ke Ж (c)

To a solution of 2,2-di(cyclobutyloethylmethanesulfonate (1.75 g, 7.532 mmol) in dimethyl sulfoxide (23 mL) was added solid sodium cyano (290 μL, 9.468 mmol) under a nitrogen atmosphere. The mixture was stirred at 70 "C. The reaction turned into a light a yellow suspension upon heating, and then to a light yellow suspension with the passage of time. The reaction was left under stirring for 17 h at 70 "C. Then the reaction mixture was poured into cold water (25 ml) and extracted with diethyl ether (3 x 25 ml). The combined organic layers were washed with water (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product, 3,3-di(cyclobutyl)propanenitrile (1.2 g, 9895) as a clear pale- amber color, which was used without additional purification. TN NMR (400 MHz, chloroform-a) b 3.48 (d, U - 7.0 Hu, 1H), 2.38 - 2.21 (t, 2H), 2.10 - 1.92 (t, 2H), 1.92 - 1.64 (t, 8H), 1.63 - 1.48 (t, 2H), 1.21 (I, U - 7.0 Hz, 2H).

Stage 3: 3,3-di(cyclobutyl)propionic acid

I m in

To a solution of 3,3-di(cyclobutyl)propanenitrile (1.2 g, 7.350 mmol) in ethanol (18 mL) was added sodium hydroxide (12.5 mL, 6 M, 75.00 mmol). The resulting light-amber solution was heated to 70 "C for 3 days. Solid sodium hydroxide (3 g, 75.01 mmol) was added and the reaction was stirred for additional 3 days at 100 "C. Ethanol was evaporated and the pH of the aqueous layer was adjusted to 1 by adding 5 M hydrochloric acid. The mixture was then extracted with diethyl ether (3 x 20 ml). The organic extract was dried over sodium sulfate, filtered and concentrated to obtain 3,3-di(cyclobutyl)propanoic acid (1 g, 75 95) as a light orange thick oil. IN NMR (400 MHz, chloroform-4) 5 2.16 (dddd, Y - 13.0, 9.0, 5.4, 2.5 Hz, 2H), 2.10 (d, Y - 6.3 Hz, 2H), 1.99-1.87 (m, 5H), 1.86-1.60 (m, 8H).

Stage 4: 3,3-di(cyclobutyl)propan-1-ol one one - -- 35 (c)

Lithium aluminum hydride (300 mg, 8.844 mmol) (granules) was suspended in tetrahydrofuran (15 mL) and stirred at room temperature for 30 minutes, after which the granules formed a suspension. The mixture was then cooled in an ice/water bath and 3,3-di(cyclobutyl)propanoic acid (988 mg, 5.421 mmol) in tetrahydrofuran (7.2 mL) was added dropwise over 15 minutes, maintaining the reaction temperature at 20°C. Mixtures allowed to stir for a total of 72 h, gradually warming to ambient temperature.The mixture was cooled in an ice bath and sequentially slowly quenched with water (830 μL, 46.07 mmol), then with sodium hydroxide (830 μL of 6 M, 4.980 mmol), and then with water ( 2.5 mL, 138.8 mmol).The mixture was stirred until the gray suspension was completely converted to a white granular suspension which was filtered through Celite. The solid was washed with ether.

The filtrate was concentrated by mass at 90 mbar and a water bath at 30 °C, diluted with diethyl ether, dried (magnesium sulfate), filtered and concentrated by mass, obtaining 3,3-di(cyclobutyl)propan-1-ol (868 mg, 9595 ) in the form of a colorless liquid. TN NMR (400 MHz, chloroform-4) b 3.64 - 3.54 (t, 2H), 2.11 (t, U - 13.9, 9.68, 7.4, 6.0, 2.0 Hz, 2H), 2.01 - 1.84 ( t, 4H), 1.83 - 1.59 (t, 8H), 1.50 - 1.37 (t, 2H).

Stage 5: tert-butyl 3-III,3-di(cyclobutyl)propoxy|pyrazole-1-carboxylate (9) (9)

M re M... r rt wa i i-Y o - zh nt.

Zo To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (530 mg, 2.877 mmol) and 3,3-di(cyclobutyl)ipropan-i-ol (536 mg, 3.185 mmol) in tetrahydrofuran (8 ml) triphenylphosphine (830 mg, 3.164 mmol) was added. Diisopropylazodicarboxylate (680 μl, 3.454 mmol) was slowly added dropwise to this mixture over 10 min. The reaction mixture was stirred at 50 "C for 16 hours. The tetrahydrofuran was removed by mass. Toluene was added to the crude mixture to precipitate the triphenylphosphine oxide. The mixture did not form a precipitate. The clear solution was then concentrated to dryness. The thick yellow oil was dissolved in dichloromethane and purified by gradient silica gel chromatography. 0 95 to 20 95 ethyl acetate in hexane.The pure fractions were combined and concentrated to dryness to give the desired product, tert-butyl-3-N3,3-di(cyclobutyl)propoxy|pyrazole-1-carboxylate (560 mg, 58 95 ), in the form of a white solid. 1TN NMR (400 MHz, SPiogoitogit-4) b 7.82 (y, Y - 2.9 Hu, 1H), 5.85 (y, Y - 2.9 Hz, 1H), 4.21, 9) - 7.4

Hu, 2H), 2.24 - 2.11 (t, 2H), 2.02 - 1.86 (t, ZH), 1.84 - 1.64 (t, 4H), 1.61 (5, 11H), 1.51 - 1.29 (t,

1H). MO-IER t/2 calc. 334.22565, found 335.24 (M--1) k; retention time: 2.47 min. (The method of RH

IN).

Stage 6: 3-IZ,Z-di(cyclobutyl)propoxy|-1H-pyrazole c)

Ma Dona

Trifluoroacetic acid (700 μl, 9.086 mmol) was added to a solution of tert-butyl 3-III,33-di(cyclobutyl)propoxy|pyrazole-1-carboxylate (200 mg, 0.5980 mmol) in dichloromethane (2 mL).

The mixture was stirred at room temperature for 2 h. Trifluoroacetic acid was removed under reduced pressure and the obtained crude product was diluted with ethyl acetate.

The organic solution was washed with aqueous sodium bicarbonate. The aqueous layer was additionally extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness to give 3-I3,3-di(cyclobutyl)propoxy|-1H-pyrazole (140 mg, 100 95). MO-IER ip/2 calc. 234.17322, found 235.15 (M.-1); retention time: 1.9 min. (Method of RH B).

Stage 7: tert-butyl /2-chloro-6-13-3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|pyridine-3-carboxylate o

Yes, yes, yes

Ministry of baking A

Mr. Ry

SI M SI 5-47 m s

tert-butyl 2,6-dichloropyridine-3-carboxylate (275 mg, 1.108 mmol), 3-N3,3-di(cyclobutyl)propoxy|-1H-pyrazole (260 mg, 1.110 mmol) and potassium carbonate (185 mg, 1.339 mmol) were combined in anhydrous dimethyl sulfoxide (5.2 mL), 1,4-diazabicyclo|2.2.2|octane (25 mg, 0.2229 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (10 ml) and stirred for 15 min. The resulting white solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give the product as a colorless oil, tert-butyl-2-chloro-6-I3-I3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|Ipyridine-3-carboxylate (367 mg, 74 95). "IN NMR (400 MHz,

SNiogoiogt-a) b 8.35 (y, U - 2.9 Hz, 1H), 8.18 (a, Y - 8.4 Hz, 1H), 7.69 (a, Y - 8.4 Hz, 1H), 5.95 (y, y - 2.8 Hz, 1H), 4.20 (I, U - 7.5 Hu, 2H), 2.18 (H, U - 9.6, 4.4 Hz, 2H), 2.07 - 1.86 (t, AN), 1.87 - 1.35 (t, 2OH). MO-IER t/2 calc. 445.21323, found 446.29 (M'-1)x; Holding time: 0.88 min. (Way

RK I.

Zo Stage 8: 2-chloro-6-I3-IZ,Z-di(cyclobutyl)propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (c) (c) uk y: on o co - -6- k Mrya - M M si -- M si a c) -

Tert-butyl o 2-chloro-6-13-3,3-di(cyclobutyl)propoxy|pyrazol-1-yl| pyridine-3-carboxylate (367 mg, 0.8229 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1.5 mL, 19.47 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction mixture was evaporated, the resulting solid was suspended in ether, and then the ether was removed under reduced pressure. This evaporation procedure from ether was repeated twice to give 2-chloro-6-13-3,3-di(cyclobutyl)propoxy|pyrazol-1-yl| pyridine-3-carboxylic acid (300 mg, 94 95). MO-IER t/2 calc. 389.1506, found 390.22 (Ma-1)k; retention time: 1.45 min. (The method of RH U).

Stage 9: tert-butyl /(45)-4-(3-((6-(2-chloro-6-13-(33,3-di(cyclobutyl)propoxy|pyrazol-1-yl|pyridin-3- carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

MN M ro on u o M si |v "A HA

In a scintillation vial with a volume of 20 ml, 2-chloro-6-I3-3,3-di(cyclobutyl)propoxy|pyrazol-51-yl|Ipyridine-3-carboxylic acid (71 mg, 0.1821 mmol) and carbonyldiimidazole (30 mg, 0.1850 mmol) were combined in tetrahydrofuran (550 μl) and stirred for 60 min at 50 "С without a lid. After that, tert-butyl (45)-2,2-dimethyl-4-I3- (b-sulfamoyl-2-pyridyl)amino|Ipropyl|Ipyrrolidine-1-carboxylate (50 mg, 0.1212 mmol) in tetrahydrofuran (850 μL), and then 1,8-diazabicyclo/5.4.O01undec-7-ene was added (36 μl, 0.2407 mmol) and the reaction was heated at 50 "С for 16 h. The reaction mixture was allowed to cool to room temperature, then concentrated to an oily residue, which was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a shallow gradient from 100 95 dichloromethane to 2095 methanol in dichloromethane to give tert-butyl (45)-4-IZ3-C(6-C2g- chloro-6-I3-I(3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylIamino|propyl|- 2,2-dimethylpyrrolidine-1-carboxylate ( 64.5 mg, 66 95) in the form of a light yellow thick oil. MSO-IER t/72 calcd. 783.3545, found 784.46 (M'-1) k; retention time: 2.21 min. (Method RH U).

Stage 10: 2-chloro-6-(3-3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|-M-((6-(3-(35)-5,5-dimethylpyrrolidine-3- yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetate salt)

In What is it about

Tert-butyl (45)-4-I3-C6-C2-chloro-6-I3-I3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|isulfamoyl|-2-pyridyliamino| Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (64.5 mg, 0.082 mmol) was dissolved in dichloromethane (1.5 mL). Trifluoroacetic acid (235 μl, 3.050 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the obtained crude product was additionally dried under high vacuum to obtain 2-chloro-6-13-3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|Ac-((6-(3-( (35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl)|pyridin-3-

From carboxamide (trifluoroacetate salt) (53 mg, 52 95, purity 97 95) MO-IER t/: calc. 683.30206, found 684.39 (M'-1)k; Retention time: 0.86 min (method РХ 5).

Stage 11: (145)-8-I3-(3,3-dicyclobutylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 231)

(9) ogo (9) o, z dsch- Y I MN

TRA U

AND

A mixture of 2-chloro-6-(3-3,3-di(cyclobutyl)propoxy|pyrazol-1-yl|-M-((6-(3-(35)-5,5-dimethylpyrrolidin-3-yl) propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetate salt) (52 mg, 0.07599 mmol), potassium carbonate (55 mg, 0.3980 mmol), cesium fluoride (25 mg, 0.1646 mmol ), molecular sieves Z A and dimethyl sulfoxide (3.6 ml) were placed in a vial, purged with nitrogen, closed with a lid, heated to 165 °C and stirred for 16 hours.

The reaction mixture was cooled to room temperature and the mixture was filtered. The filtrate was purified by reversed-phase HPLC-MS using a Hypa C18 column (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art.: 00С-4252-00-АЧ), running with a double gradient of 30- 99,956 mobile phase B in 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 1300 μl and column temperature - 25 " C) to obtain in the form of a white solid (145)-8-|3-(3,3-dicyclobutylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9 . 231) (15.5 mg, 32 do). IN NMR (400 MHz, Spiogotogpt-a) b 9.96 (5, 1H), 8.19 (y, U - 2.68 Hz, 1H), 8.07 (a, U - 8.4 Hz . . In - 14.1 Gu, 1H), 3 .06 (I, U - 9.8 Gu, 1H), 2.26 - 2.11 (t, 2H), 2.09 (aa, 9 - 12.3, 7.9 Hz, 1H), 2.03 -1.86 (t, ЗН), 1.80 (5, 1H ), 1.82 - 1.72 (t, 2H), 1.76 - 1.62 (t, ZN), 1.62 (a,

U - 3.3 Gu, 7H), 1.46 (aa, y - 14.2, 9.0, 5.2 Hz, 1H), 1.26 (5, 1H), several aliphatic protons are hidden by the water peak. MO-IER t/2 calc. 647.3254, found 648.38 (M--1)k; Holding time: 1.89 min. (The method of RH U).

Example 69: Preparation of 7,7-dimethyl-11-(3-13-1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22-pentaazatetracyclo|16.3.1.15,8.09,14)|tricose-1 (22), 9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (Compound 234) and 7, 7-dimethyl-11-(3-13-11- (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15 ,8.09,14|tricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (Compound 235) o GI Z OM5 on ov Vosm

U vier1 U vier2 nm ver3 VosM Ier4 ge gray

Mo,

B Ge)

WATER What | C is A ul MU si -7itnihk

M and (c) re -4

AND

Co., Ltd.) of

PKD SM

SOSO do re Me -060OIK in MU cho berz sh- Mn sh- Mn - Sa in SNEKfYA in, o ws mm am es 4 ep in Mom 2 m sche NE: m | - N. Mich

Stage 1: 3-(2-methyl-2-nitropropyl)dihydrofuran-2-one (c) (c) (c)

O--d same

MO,

To a mixture of 2-nitropropane (49 ml, 2.2 mol) and 1,8-diazabicyclo/5.4.0)undec-7-ene (4.1 ml, 0.1 mol) under a nitrogen atmosphere was added 3-methylene dihydrofuran-2 (ZN)-one (75 g, 776 mmol) dropwise over 45 min. The addition is exothermic: the temperature was maintained below 90 C, controlling the rate of addition during the reaction. The mixture was stirred for another 4 hours at 85 C, cooled to room temperature and diluted with ethyl acetate (500 ml) and 1 M hydrochloric acid (60 ml). The organic phase was separated, dried over sodium sulfate, filtered and concentrated under vacuum to obtain a dark oil.

Trituration with a small amount of methyl tert-butyl ether gave a large amount of white precipitate, which was collected by filtration to give 3-(2-methyl-2-nitropropyl)dihydrofuran-2-one (75.6 g, yield 73 95) as a white solid . The material was used at the next stage without additional purification. MSO-IER t/: calc. 187.2, found 188.0 (M--1) k.

Holding time: 2.34 min. (The method of RK M).

Stage 2: 3-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (c) (o); he (c) --k NM

MO,

A 1.5-liter Parr reactor was charged with Raney nickel suspension (10 g), 3-(2-methyl-2-nitropropyl)dihydrofuran-2-one (75.6 g, 0.86 mol), and ethanol (1.2 l). The reactor was hermetically closed and heated to 60 "C under a hydrogen pressure of 2 bar for 16 hours, and then cooled to room temperature. About 100 g of celite was added to the reactor. The resulting suspension was filtered through a thin layer of silica gel and washed with ethanol (200 ml). Vol' the combined filtrates were concentrated under vacuum to give 3-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (64.5 g, quantitative yield) as a white solid. The crude material was used in the next step without further purification. MS -IR t/: calcd 157.2, found 158.1 (M--1) gk Retention time: 1.38 min (Method RH M).

Stage 3: tert-butyl ester (4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid (c) one one

NM --- Towers

Lithium aluminum hydride (53.9 g, 1.4 mol) was added to a mixture of 3-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (55.8 g, 0.36 mol) and tetrahydrofuran (710 mL). The addition was carried out in small portions over 45 minutes to avoid excessive hydrogen evolution. The mixture was heated under reflux in a nitrogen atmosphere for 22 hours. The mixture was allowed to cool to room temperature and carefully quenched by adding sodium sulfate decahydrate (300 g). The obtained gray suspension was filtered and the solids were washed with tetrahydrofuran (500 ml). Dit-butyl dicarbonate (52.3 g, 225 mmol) was added to the combined filtrates (1.2 L). The resulting mixture was stirred for 24 hours. at room temperature. The reaction mixture was concentrated and purified by chromatography on silica gel using a gradient of 0-

100 95 of ethyl acetate in hexane to obtain tert-butyl ester (4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid) in the form of a light-colored oil (40.8 g, yield 74,905). MO-

IER t/2 calc. 243.3, found 244.1 (M.-1)k. Holding time: 4.01 min. (The method of RK M).

Stage 4: tert-butyl ester of 4-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid OM5

Be --- Towers

4-(2-Hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ether (32.1 g, 132 mmol) and triethylamine (36.8 mL, 264 mmol) were dissolved in dichloromethane (400 mL) and the resulting mixture was cooled in an ice water bath for 15 min. methanesulfonyl chloride (11.3 mL, 145 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes. The reaction was quenched by adding saturated aqueous sodium bicarbonate (100 ml).

The organic layer was separated, washed with water (100 ml), dried over sodium sulfate, filtered and concentrated to obtain tert-butyl ester of 4-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid in the form of an orange oil. (41.6 g, yield 98 95). The material was used at the next stage without additional purification. MO-IER t/2 calc. 321.4, found 322.2 (MaA1)k. Holding time: 4.88 min. (Way

RK M).

Stage 5: 4-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

OoM5

VosmM MN,

VB33B5- southern part of VosM

A 1.5-liter Parr reactor was charged with 4-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (32.4 g, 101 mmol), dioxane (640 mL), and 30 95 hydroxide ammonium (640 ml). The solution was then hermetically closed and heated to 50 "C for 18 h. The reaction mixture was concentrated under reduced pressure until most of the dioxane was removed, and then dichloromethane (1 L) was added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane ( 2 x 250 mL) and removed. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0-15 96 methanol in dichloromethane containing 5 mL/liter 30 90 ammonium hydroxide, with obtaining tert-butyl ester of 4-(2-aminoethyl)-2,2-dimethylpyrrolidine-1 carboxylic acid

Zo (20.6 g, yield 66 Fo) in the form of a light-colored oil. IN NMR (500 MHz, SOSIZ) b (rrit): 3.66 (a, 1H), 2.88 (p, 1), 2.69 (t, 2H), 2.15 (t, 1H), 1.88 (t, 1H), 1.48- 1.14 (t, 20Н). MO-IER t/2 calc. 242.3, found 243.0 (M--1)k. Holding time: 3.06 min. (The method of RK M).

Stage 6: tert-butyl 2,2-dimethyl-4-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate he-KZHO 5,/ nm | сх

MN, river M.

VosM and Nam ---k

M MN

E Bash b-Fluoropyridine-2-sulfonamide (2.089 g, 11.86 mmol) and dimethyl sulfoxide (24 mL) were added to a 20 mL microwavable vessel. Potassium carbonate (8.60 g, 62.23 mmol) and tert-butyl-4-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (3.00 g, 12.38 mmol) were added, and the vial closed and heated to 100 "C on a hot plate for 4 hours. The reaction mixture was filtered, then diluted with ethyl acetate and washed with a 1M solution of citric acid, and after --

saline solution. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 80 95 ethyl acetate in hexane to give tert-butyl-2,2-dimethyl-4 as a white solid -(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (1.475 g, 31 95). MO-IER t/» cal. 398.19876, found 399.2 (Ma1) k, holding time: 1.55 min (Method RH B).

Stage 7: tert-butyl 4-(2-(6-(2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridylamino|ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Ko) i what: to her and Й B ge uv: and vs uva U "U uv | M si | chn du M si and d- MN va VODY BEDY

2-chloro-6-I3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (361 mg, 0.9262 mmol) and freshly recrystallized carbonyldiimidazole (188 mg , 1.159 mmol). Tetrahydrofuran (5.5 ml) was added and the reaction mixture was heated at 40 "C for 2 hours. A solution of tert-butyl-2,2-dimethyl-4-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl) was added |pyrrolidine-1-carboxylate (370 mg, 0.284 mmol) in tetrahydrofuran (2 mL), followed by 1,8-diazabicyclo/5.4.F)undec-7-ene (450 μL, 3.009 mmol). The reaction mixture became pale- yellow and allowed to stir overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate and brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated. The crude residue was then purified by chromatography on silica gel using a gradient of 0 905 -100 Fo of ethyl acetate in hexane gives tert-butyl-4-(2-(6-((2-chloro-6-I3-T3-1P1- (trifluoromethyl)cyclopropyl|propoxy |pyrazol-1-yl|pyridin-3- carbonyl|sulfamoyl|-2-pyridylyamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (400 mg, 56 95) in the form of white foam. MO-

IER t/2 calc. 769.2636, found 770.4 (М--1)хк; retention time: 2.01 min. (Method RK 5).

Stage 8: 2-chloro-M-I(6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl|-6-I(3-I3-

P-trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (9)

Zhe x Zhe Y XX 3-3 MAO i vOosho 0-7 M si "OO "Z u M si -ya a MN a MN

God Bashi

In a round-bottomed flask containing tert-butyl-4-(2-I((6-(2g-chloro-6-I3-(3-H11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3 -carbonyl|sulfamoyl|-2-pyridylyamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (400 mg, 0.5193 mmol), dichloromethane (10 mL) and trifluoroacetic acid (2.0 mL, 25.96 The reaction was stirred for 90 min at room temperature. The reaction mixture was then evaporated to dryness. The crude reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate.

The product precipitated and some methanol was used for extraction. The organic layer was separated (not dried over sodium sulfate) and evaporated to obtain 2-chloro-M-|((6-(2- (5,5-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl|- 6 -I3-IZ-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (344 mg, 9995) as a white solid MO-IER t/2 calcd 669.2112, found 670.5 (Ma1) g, retention time: 0.94 min (Method RH 5).

Stage 9: 7,7-dimethyl-11-(3 (13-1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22 -pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1 (22), 9,11,13,18,20-hexane-15,17,17-trione (compound 233)

9 o

Z Zh S Y M

3rd and KO o- m si 606622 "In the days of M M -ya a Be and Dii

Potassium carbonate (355 mg, 2.569 mmol), cesium fluoride (156 mg, 1.027 mmol), several 3 A molecular sieves, and a solution of 2-chloro-M-((6-(2-(5.5 - dimethylpyrrolidin-3Z-yl)ethylamino|-2-pyridyl)sulfonyl)-6-I(3-(3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-Z-carboxamide) (344 mg , 0.5133 mmol) in dimethyl sulfoxide (4 mL). The reaction mixture was sealed and placed in an oil bath preheated to 150 C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC with a gradient of 50 95-99 95 acetonitrile in water (modifier 0.190 hydrochloric acid), obtaining 7,7-dimethyl-11-(3-73-H11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8, 10,16,22- pentaazatetracyclo|16.3.1.15,8.09,14|tricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 233) (138.6 mg, 43 95) as a white powder, MO-IER t/2 calcd 633.2345, found 634.3 (MA) k, retention time: 2.22 min (Method RH B).

Stage 10: 7,7-dimethyl-11-(3-13-P1-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22- pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (Compound 234) and 17,1-dimethyl -11-(3-13-(11- (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15,8.09 ,14|tricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (Compound 235)

Y ra Y Z Y Z dr Y so iv her so g , ve uva p epapisteg 1 epapisteg2

Racemic 7,7-dimethyl-11-(3-13-(1-«"trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22- pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 233) (138.6 mg, 0.2187 mmol ) was separated by chiral NKR chromatography using SPigaiRak AB-N (column 250 x 21.2 mm, particle size 5 μm) with 2895 acetonitrile: methanol (90:10, without modifier))/72 95 mobile phase of carbon dioxide at 70 ml /min, which gives as the first eluted enantiomer 7,7-dimethyl-11-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8 ,10,16,22- pentaazatetracyclo|16.3.1.15,8.09,14|tricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (Compound 234 ) (68.1 mg, 98,965). MO-IER t/72 calculated 633.2345, found 634.4

Zo (Ma1)zh; Holding time: 2.22 min. (Method of RH B). The second eluted enantiomer was 7,7-dimethyl-11-(3-13-P1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-17Ab-thia-2,8,10,16, 22-pentaazatetracyclo|16.3.1.15,8.09,14Hygtricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (Compound 235) (59.3 mg, 86 95 ). IN NMR (400 MHz, DMOO-ab) b 12.46 (5, 1H), 8.20 (9, 9 - 2.8 Hz, 1H), 7.75 (a, U - 33.8 Hz, 2H), 7.18 (5, 1H), 6.90 (y, U - 8.2 Gu, 1H), 6.82 (5, 1H), 6.11 (a, 9 - 2.68 Hz, 1H), 4.20 (1, U - 6.2 Hz, 2H), 3.72 - 3.46 (t, 1H) , 2.26 (5, 1H), 1.99 - 1.65 (t, 6H), 1.55 (5, 6H), 1.49 - 1.15 (t, 2H), 0.95 - 0.87 (t, 2H), 0.79 - 0.70 (t, 2H) , zoter rgoyup5j orzvsitgei ru 5oYimepi. MO-IER t/2 calc. 633.2345, found 634.3 (М--1)хк; Holding time: 2.22 min. (Way

RK B).

Example 70: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidin-1-yl|-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 237)

Э (c) zier 1 and ОН same c

E G MN --»

Her same /Z u i sh o, polyn o min Mn

E E

E E

Stage 1: 3-(4,4 4-trifluoro-3,3-dimethyl-butoxy)pyrrolidin-2-one

E t E HER

E E o

To a stirred solution of 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (280 mg, 1.793 mmol, contains 29 mol. 95 residual diethyl ether) and 3-bromopyrrolidin-2-one (275 mg, 1.677 mmol) (bis(trimethylsilyl)amino|potassium (7.1 ml of 0.5 M in toluene, 3.550 mmol)) was added dropwise in anhydrous tetrahydrofuran (12 ml) at a temperature from -50 "C to -60 "C for 2 minutes in the atmosphere nitrogen. After stirring for 15 minutes at this temperature, the cooling bath was removed and the flask was immediately placed in an ice-water bath at 0 °C. The reaction mixture was then allowed to warm to ambient temperature and stirring was continued overnight under a nitrogen atmosphere. To the reaction mixture was added glacial acetic acid (200 μl, 3.517 mmol) and volatiles were removed under reduced pressure. 3,3-dimethylbutoxy)pyrrolidin-2-one (238 mg, 59 95 ) in the form of dirty white solid. IN NMR (400 MHz, Veplepe-ab) b 5.87 (5, 1H), 4.13 (a, U - 9.6, 7.0 Gu, 1H), 3.42 (4, U - 9.6, 6.8 Hz, 1H), 3.39 - 3.33 ( t, 1H), 2.52 - 2.41 (t, 1H), 2.25 (01.9 - 9.6, 7.0 Hz, 1H), 1.72 (4, U - 6.9, 1.5 Hz, 2H), 1.57 - 1.43 (t, 2H) , 0.94 (а, У - 3.6 Hz, 6Н). 196 NMR (376 MHz, benzene-ab) b -78.62. MO-IER t/2 calc. 239.11331, found 240.2 (MaA1)k; retention time: 1.16 min. (Method of RH B).

Stage 2: (145)-12,12-dimethyl-8-(2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidin-1-yl|-2A6-thia-3, 9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 237 ) oh ooo

M/x o oo xx GT y. Sat Feb in « and St in, «Z Fri Mn (in) | N M - 6 (65 Zh o

E E

E E

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose was added to a vial with a volume of 4 ml. 1(23),5,7,9,19,21-hexane-2,2,4-trione (20 mg, 0.04445 mmol), 3-(4,4,4-trifluoro-3,3-dimethyl -butoxy)pyrrolidin-2-one (13 mg, 0.05434 mmol), cesium carbonate (52 mg, 0.1596 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg, 0, 006913 mmol) and anhydrous dioxane (0.7 mL) in this sequence. Nitrogen was blown through the heterogeneous mixture for 3 minutes. Then, nitrogen was added in the atmosphere

From tris(benzylideneacetone)dipalladium (0) (4 mg, 0.004368 mmol) and the mixture was purged with nitrogen for another 2 min and closed under a nitrogen atmosphere. The mixture was stirred at 108 °C overnight.

The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). Volatile substances were removed under reduced pressure, and the residue was dissolved in dimethylsulfoxide (1.5 ml) and filtered through a disc filter of a UMpaitap syringe with PTFE 0.45 μm. The sample was purified using a preparative reversed-phase HPLC-MS (Hipa C18 column (2) (75 x 30 mm, particle size 5 μm), which is sold

Rpepotepeh (art.: 00С-4252-00-АЧ), run of a double gradient of 30-99 95 acetonitrile in water for 15 minutes (hydrochloric acid as a modifier)| with the formation of (145)-12,12-dimethyl-8-(2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidin-1-yl|-2Ab-thia-3,9 . 237) (8 mg, 27 Fo) in the form of a yellowish solid. IN NMR (400 MHz, DMSO-a6) b 12.42 (5, 1H), 7.71 (da, y - 8.4, 1.9 Hz, 1H), 7.57 (da , 9 - 8.5, 7.2 Hu, 1H), 7.52 (da, U - 8.4, 6.3 Hu, 1H), 7.04 (1, 9 - 7.3, 0.9 Hz, 1H), 6.96 (a, U - 8.8 Hu, 1H) . , 1H), 2.94 (a, U - 13.2 Hz, 1H),

2.73 - 2.63 (t, 1H), 2.47 - 2.38 (t, 1H), 2.15 - 2.02 (t, 1H), 1.98 - 1.86 (t, 1H), 1.82 (09, U - 11.7, 5.1 Hz, 1H), 1.76 (Id, U - 7.0, 1.8 Hz, ЗН), 1.69 - 1.57 (t, 2Н), 1.57 (5, ЗН), 1.50 (и, У - 12.4 Hz, 1Н), 1.46 (5, ЗН), 1.29 (ad, 9 - 13.6, 12.8 Hz, 1H), 1.14 (9 - 1.9 Hz, 6H). 196 NMR (376 MHz, dimethylsulfoxide-4b) b -77.59. MO-IER t/72 calc. 652.2655, found 653.4 (M-a-1)k; retention time: 2.1 min. (Method of RH B).

Example 71: Preparation of 12,12-dimethyl-8-13-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3 ( Compound 238) (c) oh // 5 7

SWING

(in)

МН и хх on G «er 1 ---dya.

M - a- M M o ry ah 5-X (c) (c) Y - (9)

That's me Ba

M r Mak skh g y o / M M SI | n hi Mn M - Moh

G zier2 d- vda o (9) ve

Stage 1: tert-butyl 4-(2-((6-(2-chloro-6-(3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl|Ipyridin-

Z-carbonyl|isulfamoyl)|-2-pyridylyamino|ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate o (c)

КИ in t and Й k

Yi em MU si "xx

Mn 0-y de oy -- ЧО schi -, XX (c) in 2-chloro-6-I3-(2-isopropyl-3-methyl-butoxy) pyrazol-1-yl| pyridine-3-carboxylic acid (225 mg, 0.6395 mmol) and carbonyl diimidazole (111 mg, 0.684b6 mmol) were combined in anhydrous tetrahydrofuran (8 ml) and stirred for 75 min at 40 °C. Then a tetrahydrofuran solution was added (7 mL) tert-butyl-2,2-dimethyl-4-(2-((6b-sulfamoyl-2-pyridyl)amino|ethoxy|pyrrolidine-1-carboxylate) (265 MG, 0.6393 mmol) and 1, 8-diazabicyclo/5.4.F)undec-7-ene (200 μl, 1.337 mmol). The reaction was heated at 50 °C for 4 h. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with brine. Organic the layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100 95 hexanes to 75 95 ethyl acetate in hexane to give tert-butyl-4-(2- (6-C2-chloro-6-(3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino|ethoxy|-2,2-dimethylpyrrolidine-1 - carboxylate (176 mg, 3 7,905). MO-IER t/2 calc. 747.3181, found 748.41 (Ma1)f; retention time: 0.67 min. (Method of RH A).

Stage 2: 12,12-dimethyl-8-13-13-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)y-15-oxa-2A6-thia-3, 9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 238) (9) o (o)

ZY o

M. d Makh shh m" dsh- Mn M - mih --Y m y (o) v r ve roi o (9) ve

tert-butyl 4-(2-((6-(2-chloro-6-I3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino |ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate (176 mg, 0.2352 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (550 μl, 7.14 mmol) was added to the mixture. The reaction solution was stirred at room temperature 30 min.

The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was combined with potassium carbonate (195 mg, 1.41 mmol), cesium fluoride (53.6 mg, 0.353 mmol), 3 A molecular sieves, and dimethyl sulfoxide (3 mL) in a vial and purged with nitrogen. The vial was closed, heated to 140 C and stirred for 20 hours. The mixture was cooled to room temperature. The reaction mixture was filtered and then purified by reverse phase preparative chromatography (C18 column, 30 95 to 99 95 acetonitrile (no modifier) in water (HmM hydrochloric acid) for 30 minutes) to give 12712 -dimethyl-8 -(3-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)-15-oxa-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (compound 238) (64 mg, 44 95) IN NMR (400 MHz, DMSO-ab) b 12.59 (5, 1H), 8.20 (y,9 - 2.8 Hz, 1H), 7.79 (a, U - 8.2 Hz, 1H), 7.59 (da, U - 8.5 , 7.2 Hz, 1H), 7.13 (a, 9U -9.1 Hz, 1H), 7.10 (a, - 7.2 Hz, 1H), 6.96 (a, U - 8.2 Hz, 1H), 6.71 (a, 9 - 8.5 Hz . (y, U - 12.7 Hz, 1H), 3.22 (5, 1H), 2.87 (a, 9 - 9.4 Hz, 1Hn), 2.08 (da, U - 11.4, 6.0 Hz, 1H), 1.89 (ad, U - 13.2, 6.6 Hz, 2H), 1.79 (Y, 9 10.9 Hz, 1H), 1.58 (y, U - 9.7 Hz, 6H), 1.42 - 1.30 (t, 2H), 0.98 (a, U - 6.8 Hz, 6H), 0.92 (a, 9 - 6.8

Hz, 6H). MO-IER t/ calc. 611.289, found 612.2 (M--1)k; Holding time: 2.29 min. (The method of RH

Koo) B).

Example 72: Preparation of (145)-8-13-(2-(adamantan-1-yl)ethoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11, 18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 240 ) and (145)-8-73-(2-(adamantan-1-yl)ethoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18, 23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (diastereomer 2) (Compound 241 ) y o M / z on y -u wai y em po shi

99 , about PK hi M shany | Wed g

N pt0-eV8IK- silk pod der

Chiazigeoteg 1 diazegeoteg 2

Stage 1: 3-(2-(1-adamantyl)ethoxy|pyrrolidin-2-one (c)one

Vg MN

To a solution of 1-adamantanethanol (1.099 g, 6.098 mmol) and 3-bromopyrrolidin-2-one (1.00 g, 6.098 mmol) in anhydrous tetrahydrofuran (50 mL) was added potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran , 12.8 ml, 12.8 mmol) at -50 "C dropwise. The reaction mixture was stirred at the same temperature for 20 minutes, then in an ice bath for 3 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride (50 ml) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated with hexane and the resulting solid was collected by filtration to give 3-(2-adamantane -1-ylethoxy)pyrrolidin-2-one (1.192 g, 74595) as an off-white solid. 1 H-NMR (250 MHz, dimethyl sulfoxide-a 6) a (ppm): 7.78 (s , width, 1H), 3.81 (m, 2H), 3.51 (sq, t - 8.8 Hz, 1H), 3.11 (m, 2H), 2.27 (m, 1H), 1 .90- 1.40 (m, 16H), 1.30 (t, U - 7.3 Hz, 2H). MO-IER t/2 calc. 263.19 , found 263.8 (M--1) w. Holding time: 5.24 min. (Method РХ 0).

Stage 2: (145)-8-(3-(2-(adamantan-1-yl)ethoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 240) and (145)-8--3-(2-(adamantan-1-yl)ethoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11, 18,23- pentaazatetracyclo!|1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) Compound 241) o MA o dO shcha / Theirs

ACT

990 PC ( M ev fa, - z y -

MN to Chiaviegeoteg 1 diaziegeoteg 2.

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (35 mg, 0.07779 mmol), 3-(2-(1-adamantyl)ethoxy|pyrrolidine-2- on (29 mg, 0.1101 mmol), Rag(ava)z (11 mg, 0.01201 mmol), xanthophos (9 mg, 0.01555 mmol), cesium carbonate (129 mg, 0.3959 mmol) and anhydrous dioxane (0.5 ml). The mixture was purged with nitrogen for about 3 minutes, closed with a lid and stirred at 120 "C for 14 hours. The organic solvent was concentrated,

By blowing the ampoule with nitrogen. The residue was diluted with dimethyl sulfoxide (900 μl), microfiltered and subjected to reversed-phase preparative HPLC (C18) using a gradient of acetonitrile in water (from 30 to 9995 in 15 min) and hydrochloric acid as a modifier. Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane (1X) and ethyl acetate (2X) and the organic phases were combined and dried over sodium sulfate. Filtration followed by evaporation of the solvents afforded a solid which was further purified by flash chromatography on silica gel using a gradient of methanol (095 to 595 over 30 minutes) in dichloromethane. The pure fractions were combined and the solvents were evaporated. The residue was triturated with dichloromethane/hexane and the solvents were evaporated to give a mixture of diastereomers, which were separated by chiral NCR (spigadybe! 09U-H (250x10 mm), 5 μM column; mobile phase: 2495 acetonitrile/methanol (90:10, 20 mM MNH ), 76 to carbon dioxide, 10 mL/min; 14 mg/mL in acetonitrile:methanol:dimethylsulfoxide (81:9:10); injection volume 70 μL, 100 bar).

The first eluted diastereomer was (145)-8-(3-(2-(adamantan-1-yl)ethoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11 ,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1 ) (Compound 240) (6.1 mg, 22 95, 98 95 ee). IN NMR (400 MHz, DMSO-ab) b 12.45 (rgoas 5, 1H), 7.69 (a, U - 8.4 Hz, 1H), 7.60 - 7.44 (t, 2H), 7.03 (a, 9 - 7.2 Gu, 1H ), 6.94 (Big 5, 1H), 6.68 (ha, u - 8.5 Hz, 1H), 4.21, -8.0 Hz, 1H), 4.02 (I, U - 9.5 Hz, 1H), 3.97 - 3.82 (t, 2H ), 3.74 - 3.65 (t, 1H), 3.64 - 3.53 (t, 1H), 3.12 (rg 5, 1H), 2.93 (y, U - 13.3 Hz, 1H), 2.77 - 2.64 (t, 1H), 2.45 - 2.34 (t, 1H), 2.17 - 2.03 (t, 1H), 2.00 - 1.71 (t, 6H), 1.70 - 1.39 (t, 19H), 1.40 - 1.13 (t, 5H).

MO-IER t/2 calc. 676.3407, found 677.4 (Ma1)j; retention time: 2.42 min. (Method of RH B).

The second eluted diastereomer was (145)-8-13-(2-(pyrazol-1-yluethoxy|-2-oxopyrrolidin-1-yl).12,12-dimethyl-2A6-thia-3,9,11,18, 23-pentaazatetracycloyl17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 241 ) (5.1 mg, 17 Uyu, 93,905 ev). 1TH NMR (400 MHz, dimethylsulfoxide-ab) b 12.44 (broad c, 1H)), 7.70 (a, U - 8.4 Hz, 1H), 7.61 (- 7.49 (t, 2H), 7.04 (y, 9 - 7.2 Hz, 1H), 7.00 - 6.89 (rg t, 1H), 6.70 (a, 9U - 8.5 Gu, 1H), 4.26 (i,

U - 8.2 Gu, 1H), 3.98 - 3.82 (t, ZN), 3.76 (d, y - 8.5 Hz, 1H), 3.58 (d, U - 7.7 Hz, 1H), 3.10 (Bg 5, 1H), 2.94 (rga, y - 13.3 Hz, 1H), 2.74 - 2.63 (t, 1H), 2.47 - 2.34 (t, 1H), 2.10 (horn 5, 1H), 1.95 - 1.69 (t, 6H), 1.68 - 1.39 ( t, 19Н), 1.37 - 1.18 (t, 5Н). MO-IER t/2 calc. 676.3407, found 677.4 (Ma1)xk; Retention time: 2.41 min (method RH B).

From Example 13: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-13-11-(trifluoromethyl)cyclopropyl|propoxy)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1 ) (Compound 242) and (145)-12,12-dimethyl-8-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)pyrrolidin-1-yl)-2A6-thia-3, 9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( diastereomer 2) (Compound 243) at 90.0

M o t dk AH also | and m- zivier2 ooo o KYA is AKT co

M / H - mA / y Mi - nu Be M t I odya et Vode diaviegeoteg 1 diaziegeoteg 2

Stage 1: 3-IZ3-11-"trifluoromethyl)cyclopropyl|propoxy|pyrrolidin-2-one about (c) and Vg MNO ----k 3

3-(1-(trifluoromethyl)cyclopropyl|propan-1-ol (450 mg, 2.676 mmol), 3-bromopyrrolidin-2-one (442 mg,

2.695 mmol) and anhydrous tetrahydrofuran (12 ml). The mixture was cooled to -50 "C. (bis(trimethylsilyl)amino|potassium (11.3 ml of 0.5 M in toluene, 5.650 mmol)) was added dropwise over 5 minutes and the yellow mixture was stirred at -50 "C for 15-20 minutes, then in an ice bath at 0"C for at least 3 hours. The reaction mixture was stirred in an ice bath, which was allowed to slowly warm to room temperature. After 16 hours, the mixture was cooled to 0"C, then glacial acetic acid (250 µL, 4.396 mmol), yielding a pale brown suspension. Brine (75 mL) and ethyl acetate (75 mL) were added, and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2 X 25 mL). The combined organic extracts were dried over with sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified by chromatography on silica gel (0 95 -15 9o gradient methanol in dichloromethane for 30 min) to obtain the desired 3-I3-P1-("trifluoromethyl)cyclopropyl|Ipropoxy|pyrrolidin-2-one (555 mg, 83 95 ) as an off-white solid. 1H NMR (400 MHz, Spiogoitogt-a) b 6.65 (Bgoaa 5, 1H), 3.95 (aa, 9 - 7.7, 7.0 Hu, 1H), 3.84 (a, y - 9.2, 6.2 Hz, 1H), 3.54 (4 , In - 9.2, 6.3

Hz, 1H), 3.41 (dada, y - 9.7, 8.5, 3.7, 1.1 Hz, 1H), 3.33 - 3.23 (t, 1H), 2.40 (ai, U - 13.1, 7.6, 3.7 Gu, 1H), 2.09 - 1.96 (t, 1H), 1.80 - 1.69 (t, 2H), 1.69 - 1.52 (t, 2H), 0.98 - 0.85 (t, 2H), 0.64 - 0.47 (t, 2H). MO-IER t/2 calc. 251.11331, found 252.1 (MAT); retention time: 1.32 min. (The method of RH

IN).

Stage 2: (145)-12,12-dimethyl-8-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|propoxy)pyrrolidin-1-yl)-2A6-thia-3,9,11 ,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 242) and (145 )-12,12-dimethyl-8-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|propoxy)pyrrolidin-1-yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 243) at 9.0

M o y shcha / Their - Y xx | y m-sh 0 -- Zh uche di si M Mod o o. (c) ku M o -O r EH Ii i i zhk

And and x | y M- eh 5 t ve MO t vod - dl diaziegeoteg 1 diaviegeoteg 2

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (32 mg, 0.07112 mmol), 3-I3-1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrrolidin-2-one (25 mg, 0.09950

Zo mmol), Rag(ava)Zz (11 mg, 0.01201 mmol), xanthophos (11 mg, 0.01901 mmol), cesium carbonate (110 mg, 0.3376 mmol) and anhydrous dioxane (0.6 mL). The mixture was purged with nitrogen for approximately 3 minutes, closed with a lid, and stirred at 120 "C for 16 hours. The organic solvent was concentrated by purging the vial with nitrogen. The reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered, and subjected to reversed-phase preparative HPLC (C18) using gradient of acetonitrile in water (from 30 to 99 95 in 15 min) and hydrochloric acid as a modifier. The pure fractions were collected and the organic solvents were evaporated. The resulting aqueous solution was extracted with ethyl acetate (3x), and the combined organic phases were dried over sodium sulfate. Filtration and evaporation of the solvents gave a solid which was purified by flash chromatography on silica gel using a gradient of methanol (0 95 to 5 95 over 30 minutes) in dichloromethane. The pure fractions were combined and the solvents were evaporated. The residue was triturated with dichloromethane/hexane and the solvents evaporated, obtaining a mixture of diastereomers, which were separated using chiral NCR (SpigaIS is! 0U-H (250X10 mm), 5 μM column; mobile phase: 24 95 acetonitrile/methanol (90:10; 20 MM MNH), 76 95 carbon dioxide, 10 ml/min; concentration: 23 mg/ml: in acetonitrile/methanol (90:10; 20 mM MNUZ); injection volume 70 μl, 100 bar). The first eluted diastereomer was (145)-12,12-dimethyl-8-(2-oxo-3-73-P1-(trifluoromethyl)cyclopropyl|propoxy)pyrrolidin-1-yl)-2Ab-thia-3,9,11 ,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) ( Compound 242) (6.3 mg, 26 95). MSO-IER t/2 calc. 664.2655, found 665.4 (M--1)4; Holding time: 2.05 min. (Method of RH B). The second eluted diastereomer was (145)-12,12-dimethyl-8-(2-oxo-3-13-11-(trifluoromethyl)cyclopropyl|propoxy)pyrrolidin-1-yl)-2A6-thia-3,9,11 ,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 243) (5,2 mg, 22 95). IN NMR (400 MHz, DMSO-46) b 12.45 (Bgoaa 5, 1H), 7.70 (a, 9 - 8.4 Hu, 1H), 7.61 - 7.47 (t, 2H), 7.04 (a, 9 - 7.2 Hz, 1H ), 6.96 (5, 1H), 6.69 (a, 9 - 8.5 Hz, 1H), 4.30 (I, U - 8.4 Gu, 1H), 3.92 (I, U - 9.8 Hz, 2H), 3.82 - 3.70 (t , 2H), 3.60 - 3.49 (t, 1H), 3.10 (Bg 5, 1H), 2.93 (y, U - 13.3 Hz, 1H), 2.74 - 2.64 (t, 1H), 2.48 - 2.36 (t, 1H) . , 2H). MO-IER t/: calc. 664.2655, found 665.4 (M--1)f; retention time: 2.06 min. (The method of RH

IN).

Example 74: Preparation of (145)-8-43-Cadamantan-1-yl)methoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 244) and (145 )-8-13-Cadamantan-1-yllomethoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111, 14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 245) at 9.0

M on y | y - zivr2 t -u ber Fu si and kozh OD at 9.0 and KUya 9 t M zhk ii sh i» zhk yo. Vch m y mm dya de diaziegeoteg 1 diaziegeoteg 2

Stage 1: 3-(1-adamantylmethoxy)pyrrolidin-2-one o (c) one and - -

Vg MH ---

A 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (6.3 ml, 6.30 mmol) at -60 °C. The reaction mixture was stirred at this temperature for 20 minutes, then raised to 0 °C and stirred for another 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with saline (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated.

The residue was triturated with hexane (30 mL) and the solid formed was collected by filtration to give 3-(adamantan-1-ylethoxy)pyrrolidin-2-one (0.594 d, 7995) as a white solid

From substance. TN-NMR (250 MHz, dimethylsulfoxide-a6) a (ppm): 7.77 (s, shr, 1H), 3.82 (t, y - 7.3 Hz, 1TN), 3.31 ( m, 1H), 3.11 (m, 2H), 3.30 (d, U - 9 Hz, 1H), 2.26 (m, 1H), 1.92-1.48 (m, 16H). MO-

IER t/2 calc. 249.17, found 250.2 (M--1)k. Holding time: 4.97 min. (Method РХ 0).

Stage 2: (145)-8-13-Cadamantan-1-yl)methoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,1O|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 244) and (145)-8--3-K(adamantan-1-yl)methoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo !| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 245)

o MA o db ra AH x | K M- -- - zh (c) MN s BU ry o 9,o o --- ra Uh I y s.

UK l

MN diaztegeoteg 1 diaztegeoteg 2

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (35 mg, 0.07779 mmol), 3-(1-adamantylmethoxy)pyrrolidin-2-one (30 mg, 0.1203 mmol ), Rag(ara)z (10 mg, 0.01092 mmol), xanthophos (12 mg, 0.02074 mmol), cesium carbonate (130 mg, 0.3990 mmol) and anhydrous dioxane (0.6 ml). The mixture was purged with nitrogen for approximately 3 minutes, capped, and stirred at 120°C for 22 hours. The organic solvent was concentrated by purging the vial with nitrogen. The reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered, and subjected to reversed-phase preparative HPLC (C18) using gradient of acetonitrile in water (3095 to 9995 in 15 min) and hydrochloric acid as modifier (950 μl injection). The pure fractions were collected and the organic solvents were evaporated. The solid was extracted with ethyl acetate (2X) and the organic phase was dried over sodium sulfate. Filtration, followed by evaporation of the solvents gave a solid which was purified by flash chromatography on silica gel using a gradient of methanol (0 95 to 5 95 over 30 min) in dichloromethane.The pure fractions were collected and the solvents were evaporated.

The residue was triturated with dichloromethane/hexane and the solvents were evaporated to give a mixture of diastereomers, which were separated by chiral NCR (SpigaISe!0O-H (250 x 10 mm), 5

MKM column; mobile phase 31 95 acetonitrile/umethanol (90:10, 20 mM MNH), 69 95 carbon dioxide, 10 ml/min; concentration 23 mg/ml in acetonitrile/methanol (90:10; 20 mM MNUZ); injection volume 70 μl, 100 bar)". The first eluted diastereomer was (145)-8-13-

Cadamantan-1-yl)methoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 244) (6.3 mg, 23 95). IN NMR (400 MHz, DMSO-46) b 12.46 (Bgoaa 5, 1H), 7.70 (a, 9 - 8.4 Hz, 1H), 7.56 (I, U - 7.9 Hz, 1H), 7.50 (j, U - 8.4 Hz, 1H), 7.03 (a, y - 7.2 Hz, 1H), 6.95 (Bg 5, 1H), 6.69 (a, U - 68.4 Hz, 1H), 4.19 (1.9 - 8.1 Hz, 1H), 4.02 (I, U - 9.3 Hu, 1H), 3.98 - 3.84 (t, 1H), 3.69 (ai, U - 10.4, 7.5 Hz, 1H), 3.41 (a, U - 9.0 Hu, 2H), 3.11 (a, U - 9.0 Gu, 2H), 2.93 (9.9 2 13.2 Hz, 1H), 2.76 - 2.64 (t, 1H), 2.45 - 2.36 (t, 1H), 2.10 (reg 5, 1H), 1.98 - 1.85 ( t, 4H), 1.85 - 1.41 (t, 22H), 1.34 - 1.26 (t, 1H). MO-IER t/2 calc. 662.325, found 663.5 (Ma1)k; Time

From maintenance: 2.41 min. (Method of RH B). The second eluted diastereomer was (145)-8-(3-

Cadamantan-1-yl)methoxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 245) (5,6 mg, 20 95). IN NMR (400 MHz, DMSO-46) b 12.45 (Bgoaa 5, 1H), 7.70 (a, 9 - 8.4 Hz, 1H), 7.61 - 7.48 (t, 2H), 7.04 (a, U - 7.2 Hz, 1H ), 6.95 (Bg 5, 1H), 6.69 (y, 9 - 8.5 Hz, 1H), 4.24 (1. 9 - 8.3 Hu, 1H), 3.92 (I, 9 - 9.5 Hu, 2H), 3.77 (d, In - 9.4, 8.68 Hz, 1H), 3.41 (a,

U - 8.9 Hz, 2H), 3.10 (a, U - 9.0 Hz, 2H), 2.93 (8, U - 13.3 Hz, 1H), 2.77 - 2.64 (t, 1H), 2.46 - 2.38 (t, 1H), 2.10 (reg 5, 1H), 1.96 - 1.72 (t, 6H), 1.72 - 1.42 (t, 2OH), 1.38 - 1.25 (t, 1H).

MO-ER t/2 calc. 662.325, found 663.5 (M--1) k; retention time: 2.41 min. (Method of RH B).

Example 75: Preparation of (145)-8-13-(4,4-dimethylpentyl)oxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18,23 -pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 246) and ( 145)-8-(3-K(4,4-dimethylpentyl)oxy|-2-oxopyrrolidin-1-yl)-412,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo! 17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 247)

(c) he 5ier 1 i li Vg MNO-----i (9) (9) ra viie

ЗАС D t zi sh y? -- zh-k si M si i o o o (c)

KI

(Her at 5 o'clock you / x saw 5

АХА this -- і6 ny і I M dr» М M si і Hu et o ol, GI he

She r Is" those

N o s | c Iv zierb u o B si MAX vir 7 i Mn MN

Be gne ra at 9.0 and (c) KU o r ra Z aty LE nedo Schrode

M j M-- k M M

With /7 " ozh, In /t od

MN diazygeoteg 1 diazygeoteg 2

Stage 1: 3-(4,4-dimethylpentoxy)pyrrolidin-2-one

4,4-dimethylpentan-1-ol (0.97 g, 8.348 mmol), 3-bromopyrrolidin-2-one (1.41 g, 8.598 mmol) and anhydrous tetrahydrofuran (5 ml ). The mixture was cooled in an ice-water bath and a solution of KNMO5 (17 mL of 1 M, 17.00 mmol) was added over 10 min (the solution quickly turned brown). The mixture was stirred in a cooling bath, which was allowed to warm to room temperature overnight. After 24 hours, the reaction mixture was cooled in an ice water bath and treated with acetic acid (1 mL, 17.58 mmol) and brine (50 mL). The product was extracted with ethyl acetate (2 x 40 ml). The combined organic extracts were washed with sodium sulfate, filtered and the solvents evaporated to give crude material (430 mg). The residue was subjected to flash chromatography on silica gel using a gradient of methanol (from 095 to 1595 in 20 min) in dichloromethane to give 3-(4,4-dimethylpentoxy)pyrrolidin-2-one (239 mg, 14 95) as a beige solid substances 1TN NMR (400 MHz, Spiogotogt-a) b 5.85 (Bgoai 5, 1H), 3.97 (ai, 9 - 7.7, 6.9 Hz, 1H), 3.83 (aa, U - 8.9, 7.4, 6.6 Gu, 1H), 3.52 (a, U - 9.0, 7.1 Hz, 1H), 3.43 (adaa, 9 - 9.6, 8.4, 3.8, 1.2 Hz, 1H), 3.29 (dada, 9 - 9.6, 7.5, 6.7, 0.68 Gu, 1H), 2.42 (aa, 9 - 13.1, 7.6, 3.9 Hz, 1H), 2.09 (aa, U - 13.0, 8.4, 6.8 Hz, 1H), 1.68 - 1.49 (t, 2H omeparrei uliy gezidtsa! zoimepi), 1.28 - 1.12 (t , 2Н), 0.88 (5, 9Н).

MO-ER t/2 calc. 199.15723, 200.2 (M--1) found; Holding time: 1.3 min. (Method of RH B).

Stage 2: Ethyl 2-chloro-6-(3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl|pyridine-3-carboxylate

A. Dova drained the DS. u di, - si M si in

Ethyl 2,6b-dichloropyridine-3-carboxylate (336 mg, 1.527 mmol) and 3 (4,4-dimethylpentoxy)pyrrolidin-2-one (287 mg, 1.440 mmol) were charged to a 100 ml flask under a nitrogen atmosphere. anhydrous M,M-dimethylformamide (b ml). Potassium carbonate (271 mg, 1.961 mmol) (325 mesh) was added followed by 1,4-diazabicyclo(2.2.2|octane (25 mg, 0.2229 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 2 days, the reaction was quenched by adding water (50 ml), then extracted with ethyl acetate (2 x 25 ml).

The organic phase was dried over sodium sulfate, filtered and the solvents were evaporated. The product was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 95 to 5095 over 20 minutes) in hexane. Pure fractions were collected and the solvents were evaporated to obtain ethyl 2-chloro-6-I3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carboxylate (358 mg, 65 95) in the form of a colorless resin. which slowly hardened. IN NMR (400

MgGu, DMOO-ab) b 8.36 (a, U - 8.6 Hz, 1H), 8.32 (a, 9 - 8.6 Hz, 1H), 4.38 - 4.26 (t, ZN), 4.02 (aa,

U - 11.1, 68.9, 2.6 Hz, 1H), 3.81 - 3.67 (t, 2H), 3.54 (a, U - 9.3, 6.6 Hz, 1H), 2.49 - 2.39 (t, 1H), 1.92 (99, U - 12.4, 8.8 Hz, 1H), 1.58 - 1.44 (t, 2H), 1.32 (9. - 7.1 Gu, ZN), 1.25 - 1.16 (t, 2H), 0.87 (5, 9H). MO-IER t/: calc. 382.16592, found 383.3 (M--1)k; Holding time: 2.26 min. (The method of RH

IN).

Stage 3: 6-(3-carboxy-3-(4,4-dimethylpentoxy)propyl|iamino|-2-chloro-pyridine-3-carboxylic acid o (c) o xxx ol son z on in m M si rt» Y and a

In a 100 ml flask, ethyl 2-chloro-6-I3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carboxylate (335 mg, 0.8749 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml) were mixed until homogeneous. Sodium hydroxide (1 mL 2 M, 2.000 mmol) (2 M aqueous) was added to the mixture, and the cloudy mixture was stirred at ambient temperature for 9 hours. Sodium hydroxide (1 ml 6 N) was added and the mixture was stirred overnight. The reaction was diluted with water (40 mL). The solution was acidified by slow addition of 6 n. of hydrochloric acid to pH 2. The solid was extracted with ethyl acetate (2 x 50 ml, 1 x 25 ml), and the combined organic phases were dried over sodium sulfate, filtered and concentrated to np mass. The residue was triturated with dichloromethane/hexane and the solvents were evaporated to give

Zo 6-(3-carboxy-3-(4,4-dimethylpentoxy)propyl|iamino|-2-chloropyridine-3-carboxylic acid (333 mg, quantitative yield) as an off-white solid. TN NMR (400 MHz . (ai, U - 8.9, 3.8 Hz, 1H), 3.50 (41, U - 8.9, 6.6 Gu, 1H), 3.42-3.36 (t, 1 H), 3.34 (rgoasy 5, rapiapyu omepParreid

M Yp mageg zidpai, 1H), 3.25 (ai, y - 8.9, 6.7 Hz, 1H), 2.00 - 1.85 (t, 1H), 1.85 - 1.73 (t, 1H), 1.52 - 1.39 (t, 2H), 1.20 - 1.12 (t, 2H), 0.84 (5, 9H). MO-IER t/2 calc. 372.1452, found 373.2 (MA) k; retention time: 1.47 min. (Method of RH B).

Stage 4: 2-chloro-6-(3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl|Ipyridine-3-carboxylic acid (c) n (c) shon son uva; -7 - ruch Y Y " Y - ro" M M sy ry

6-|((3-carboxy-3-(4,4-dimethylpentoxy)propyl|amino|-2-chloropyridine-3-carboxylic acid (281 mg, 0.7537 mmol)) was charged into a 100 ml flask under nitrogen atmosphere.

NATY (292 mg, 0.7680 mmol) and anhydrous tetrahydrofuran (b ml) (partial suspension).

Triethylamine (0.34 mL, 2.439 mmol) was added (rapidly converted to a yellow homogeneous solution) and the mixture was stirred at room temperature for 2 days. Water (30 ml) was added, followed by hydrochloric acid (200 μl 6 M, 1,200 mmol) (6 N aqueous, final pH - 4).

The resulting white solid was filtered and washed with water to obtain pure /2-chloro-6-N3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carboxylic acid (196 mg, 73 95) as a white solid. TN NMR (400 MHz, DMSO-ab) b 13.51 (5, 1H), 8.34 (a, 9 - 8.6 Hz, 1H), 8.31 (a, 9 - 68.6 Hu, 1H), 4.33 (aa, U - 8.9, 7.9 Hz, 1H), 4.01 (aa, 9 - 11.2, 8.68, 2.6 Gu, 1H), 3.82 - 3.67 (t, 2H), 3.54 (a, 9 - 9.2, 6.6 Gu, 1H), 2.48 - 2.37 (t , 1H), 1.91 (a94, 9 - 12.4, 8.9 Hz, 1H), 1.58 - 1.44 (t, 2H), 1.27 - 1.14 (t, 2H), 0.87 (5, 9H). MO-IER t/2 calc. 354.13464, found 355.3 (M--1)k; retention time: 1.91 min. (Method of RH B).

Stage 5: tert-butyl (45)-4-I3-C6-Ce-chloro-6-(3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl pyridine-3-carbonyl|Isulfamoyl| -2-pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Ge) o o 9) RA i | schi t o xx sun? ,/x in Z si o M M si MN

2-Chloro-6-(3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|Ipyridine-3-carboxylic acid (182 mg, 0.5129 mmol) was charged into a 100 ml round-bottomed flask under a nitrogen atmosphere and anhydrous tetrahydrofuran (3 mL). Carbonyl diimidazole (102 mg, 0.6291 mmol) (freshly recrystallized from tetrahydrofuran) was added and the mixture was stirred under nitrogen at room temperature for 3 h. Another 35 mg of carbonyl diimidazole was added and the mixture was stirred at room temperature for 2 h In a separate flask with a volume of 20 ml, a solution of tert-butyl (45)-2,2-dimethyl-4-3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (211 mg, 0 .5115 mmol) in anhydrous tetrahydrofuran (1.5 mL) was obtained under a nitrogen atmosphere and subsequently added via syringe to the activated ester solution.

1,8-diazabicyclo/5.4.O1undec-7-ene (0.38 mL, 2.541 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen overnight. After 2 days, the solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (20 mL) and water (20 mL). Hydrochloric acid (600 μl 6 M, 3.600 mmol) was slowly added (final pH o - 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml).

The combined extracts were washed with saline (30 ml) and dried over sodium sulfate.

After evaporation of the solvents, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate (from 0905 to 10095 over 30 minutes) in hexane to give tert-butyl (45)-4-IZ3-Cb-C2-chloro-6- And (3-(4,4-

Zo dimethylpentoxy)-2-oxopyrrolidine-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylamino|propyl|- 2,2-dimethylpyrrolidine-1-carboxylate (138 mg, 36 95, purity 90 95) in the form colorless resin.

MO-ER t/2 calc. 748.3385, found 749.5 (M--1); retention time: 2.42 min. (Method of RH B). (c) oo (o) oso o - B P OO Le

Bochade leads and MO te Me, ni bota She

MN MN ed gne ed

Stage 6: 2-chloro-6-I3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl|-M-((6-(3-(35)-5,5-dimethylpyrrolidine-3 -yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (dihydrochloride salt)

Tert-butyl (45)-4-IZ3-C(6-C2-chloro-6-(3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|Ipyridin-3- carbonyl|Isulfamoyl|-2-pyridylamino|propyl|- 2,2-dimethylpyrrolidine-1-carboxylate (138 mg, 0.1842 mmol), dichloromethane (2 mL), and hydrochloric acid (300 μL of 4 M in dioxane, 1.200 mmol) . The reaction mixture was stirred at room temperature for 3.5 h (conversion 60 95). An additional amount of hydrochloric acid (300 μl 4 M, 1.200 mmol) was added and the reaction mixture was stirred for another 2 h. Volatiles were removed by evaporation under vacuum. The residue was triturated with Kk dichloromethane/hexane and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in vacuo gave 2-chloro-6-N3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|-

M-(6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (dihydrochloride salt) (125 mg, 94595) as a white solid Product

ZB2 was used in the next stage without additional purification. MO-IER tp/:2 calc. 648.2861, found 649.4 (M.-1) k; retention time: 1.62 min. (Method of RH B).

Stage 7: (145)-8-I3 -K4,4-dimethylpentyl)oxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,1O|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 246) and (145 )-8-13-(4,4-dimethylpentyl)oxy1|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1 .111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (diastereomer 2) (Compound 247) (c) (o)

Gv) and We

M y /sh: H o xx ly Ot Mt -OI2O0Ore- re di J o 9, ,o i r rozh

M I M j M M

Mn diaviegeoteg 1 iavivtvoteg?

2-chloro-6-13-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl|-M-((6-(3-( (35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (dihydrochloride salt) (125 mg, 0.1731 mmol), anhydrous MMR (7 mL) and carbonate potassium (465 mg, 3.365 mmol) (325 mesh). The mixture was intensively stirred in a dry bath at 155 "C in a nitrogen atmosphere for 20 hours. After cooling to room temperature, the mixture was poured into chilled water (50 ml) and acidified by adding hydrochloric acid (1 mL 6 M, 6,000 mmol) (slight foaming). The resulting solid was filtered and briefly air-dried. The solid was dissolved in dichloromethane and purified by flash chromatography on silica gel using a methanol gradient (0 95 to 5 95 over 30 min ) in dichloromethane to obtain a mixture of diastereomers, which were subjected to chiral separation by NCR (SpigaISe! 00-H (250 x 10 mm), 5 μM column; mobile phase 2 4 95 acetonitrile/methanol (90:10, 20 mM MNH), 76 Fo carbon dioxide, 10 ml/min; concentration 23 mg/ml in acetonitrile/methanol (90:10; 20 mM MNH); injection volume 70 μl, 100 bar), which gives as the first eluted diastereomer (145)-8-13-(4,4-dimethylpentyl)oxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl -2Ab-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 246) (22 mg, 20 95). IN NMR (400 MHz, DMSO-ab) b 12.43 (5, 1H), 7.70 (ad, 9 - 8.4 Hz, 1H), 7.56 (1, 9 - 7.8 Hz, 1H), 7.51 (a, 9 - 8.3 Hz . 1, 9 - 8.7 Gu, 1H), 3.95-3.87 (ri

Zo t, TN), 3.81 - 3.64 (t, 2H), 3.52 (Yii, y - 9.2, 6.6 Hu, 1H), 3.12 (Bg 5, 1H), 2.94 (a, U - 13.5 Hu, 1H), 2.18 - 2.61 (t, 1H), 2.42 (ad, U - 13.0, 7.9, 6.3 Gu, 1H), 2.11 (bgoaay 5, 1H), 1.92 (dd, U - 12.3, 8.6 Hz, 1H), 1.85 - 1.68 ( t, 2H), 1.64 - 1.41 (t, 1OH), 1.36 - 1.13 (t, 4H), 0.87 (5, 9H). MO-IER t/2 calc. 612.3094, found 613.4 (M.-1)x; retention time: 2.17 min. (Method of RH B). The second eluted diastereomer was (145)-8-13-((4,4-dimethylpentyl)oxy|-2-oxopyrrolidin-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18, 23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 247) (21 mg, 1995). 1 H NMR (400 MHz, dimethylsulfoxide-ab) b 12.41 (5, 1H), 7.70 (a, U - 8.4 Hu, 1H), 7.59-7.51 (t, 2H), 7.04 (0.9 - 7.2

Gu, 1H), 6.96 (bgoaa 5, 1H), 6.70 (a, U - 68.5 Gu, 1H), 4.28 (I, U - 8.4 Hz, 1H), 3.92 (Her, U - 9.68 Hz, 2H), 3.83 - 3.68 (t, 2H), 3.52 (a, U - 9.2, 6.6 Gu, 1H), 3.10 (Bg 5, 1H), 2.94 (Bg a, U - 13.4 Hz, 1H), 2.80 - 2.59 (t, 1H ), 2.48 - 2.37 (t, 1H), 2.10 (horn 5, 1H), 1.95 - 1.68 (t, ZH), 1.64 - 1.42 (t, 1OH), 1.36 - 1.14 (t, 4H), 0.87 (5, 9H). MO-IER t/: calc. 612.3094, found 613.4 (M 1); Retention time: 2.17 min (method RH B).

Example 76: Preparation of 12,12-dimethyl-8-(3-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)y.15-oxa-2A6-thia- 3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10)hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4- trione (enantiomer 1) (Compound 248) and 12,12-dimethyl-8-13-|3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-ylIu-15-oxa- 2A6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2, of 2,4-trione (enantiomer 2) (Compound 249) o Z y. 4 x 2 ze

M s M M. -- 6 656565 -- - o-uY TM M M o o M vh m M pochatreyu Ana dk lochoyura

Stage 1: 12,12-dimethyl-8-13-13-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl)y-15-oxa-2A6-thia-3, 9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1 ) (Compound 248) and 12,12-dimethyl-8-(3-(3-methyl-2-(propan-2-yl)butoxy|- 1H-pyrazol-1-yl-15-oxa-2Ab-thia- 3,9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 249) o Z r. 4 xx 2 ze

As the earth M Y ny 9 4 ii M t o o. I m M " will chat ANT dk Lochogyura

Racemic 12,12-dimethyl-8-13-(3-methyl-2-(propan-2-yl)butoxy|-1H-pyrazol-1-yl-15-oxa-2Ab-thia-3,9,11 ,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21- hexane-2,2,4--rion (60 mg, 0.09612 mmol) was subjected to chiral NKR chromatography.

The following NCRK protocol was used: SpigaIRak A5-3 (150 X 2.1 mm), Z μm; Mobile phase 35"C: 3095 acetonitrile:methanol (90:10), 70 90 carbon dioxide. The first eluted enantiomer was 12,12-dimethyl-8-/3-(3-methyl-2-(propan-2-yl) butoxy|-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|htetracose-1(23),5( 10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 248) (21 mg, 71 95). MO-IER t/27 calcd 611.289, found 612.2 (Ma-1)zh4; Retention time: 2.30 min. (Phase B method). The second eluted enantiomer was 12,12-dimethyl-8-13-(3-methyl-2-(propan-2-yl)/ butoxy|-1H-pyrazol-1-yl)u.15-oxa-2A6-thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5 (10),6,8,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 249) (22 mg, 74 95). NR NMR (400

MHz, DMSOSO-ab) b 12.56 (5, 1H), 8.19 (a, U - 2.68 Hz, 1H), 7.78 (a, 9 - 8.2 Hz, 1H), 7.59 (ad, U - 8.5, 7.2 Hz, 1H ), 7.10 (1, 9 - 7.4 Hz, 2H), 6.95 (a, U - 8.2 Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 6.11 (a, 2.7

Hz, 1H), 4.23 (9, U - 4.8 Hz, 2H), 4.11 (i, U - 8.3 Hz, 2H), 3.88 (i, U - 12.0 Hz, 1H), 3.60 (i, U - 12.9 Hz, 1H), 3.23 (5, 1H), 3.07 (5, 1H), 2.67 (a, U - 9.4 Hu, 1H), 2.08 (ai, U 2 11.7, 5.9 Hz, 1H), 1.96 - 1.85 (t,

Zo 2H), 1.79 (I, U - 10.9 Hz, 1H), 1.58 (y, 9 - 9.2 Hz, 6H), 1.35 (p, U - 5.2 Hz, 1Hn), 0.98 (y, 9 - 6.8 Hz, 6H ), 0.92 (y, U - 6.68 Hz, 6H). MO-IER p/:2 calculation. 611.289, found 612.2 (M--1)j; Holding time: 2.29 min. (Method of RH B).

Example 77: Preparation of 11-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-17A6bthia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15, 8.09,14|Itricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (compound 251)

BB ( sun | 5 sun | 7 deya v «eri She M ih | zer? o Mn o Mn y ne I Y shi so a NU o Her u uv I y. o ud My si Iv vier4 ve te sho g. - va od

(c) (c) xx r och M Khx

M

M - rya s M M epapioteg" 1

Stage 1: tert-butyl 2,2-dimethyl-4-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (c)

Kh Mk Ko r

With 8 kh nm | west Nm

M. 02 Mu ah ---x o MN (8) with LYN uk u is! (c) epappioteg 1 5 Racemic tert-butyl-2,2-dimethyl-4-(2-(b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (1.475 g, 3.701 mmol) was separated by chiral NRC using a SpPigaIRak IS (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 3295 methanol (without modifier))/68 95 carbon dioxide at 70 mL/min, giving tert-butyl 2 as the first eluted enantiomer, 2-Dimethyl-4-(2-K(b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (enantiomer 1) (670 mg, 91 95) in the form of a white foam. MSO-IER tp/2 calcd 398.19876, found 399.3 (M--1) k, retention time: 1.59 min (Method RH B).

Stage 2: tert-butyl 4-(2-((6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|-2-pyridylIamino| ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (enantiomer 1)

I Ex 5 mn nal 5 o m se | | i - ra psch- o Mn M 2-2 Myh - o ek nt 1 5 epapioteg 1

2-Chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (147.7 mg, 0.4082 mmol), recrystallized carbonyldiimidazole (66.2 mg, 0.4083 mmol) and tetrahydrofuran (4 ml). The reaction mixture was stirred at 40 "C for 90 minutes.

Then tert-butyl-2,2-dimethyl-4-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (enantiomer 1)) (130 mg, 0.3262 mmol) was added with followed by the addition of 1,8-diazabicyclo/5.4.F)undec-7-ene (150 μL, 1.003 mmol). The reaction mixture was stirred for 2 days. The reaction was filtered and purified by HPLC (gradient 30-99 95 acetonitrile:water with modifier 0.1 95 hydrochloric acid) to obtain tert-butyl 4-(2-((6-(2-chloro-6-

13-(3,3-Dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 1) (30.4 mg, 13,965). MO-

IER t/2 calc. 741.30756, found 742.4 (M--1) k; retention time: 2.2 min. (method RH b).

Stage C: 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-((b-(2-(5,5- dimethylpyrrolidin-3-yl)ethylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (enantiomer 1)

Iii 5 o to re He

M - M ikh o-Y M si t o m MU Ts |v

And MN and MN

BaSHI haSHI epapioteg 1 epapiteg" 1

In a flask containing tert-butyl 4-(2-C(6-Ce-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 1) (30.4 mg, 0.04095 mmol) was added to dichloromethane (3 mL) and trifluoroacetic acid (125 µL, 1.622 mmol). stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness and washed with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to obtain / 2-chloro-6-|3-(3,3- dicyclopropylpropoxy)pyrazol-1-yl|-M-((6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (enantiomer 1)) (24 mg , 91 95). MO-IER t/2 calcd. 641.2551, found 642.3 (M'-1) t, retention time: 1.76 min. (Method RH B).

Stage 4: 11-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-7,7-dimethyl-1/Abthia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15, 8.09,14Hygtricose-1 (22), 9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (compound 251) o o o n | s M xx d- chn (F) y M M M vm ie rank epapiyoteg" 1 epapiyoteg 1

Potassium carbonate (35 mg, 0.2532 mmol), cesium fluoride (12 mg, 0.07900 mmol), molecular sieves Z A and a solution of 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazole- 1-il|-M-

I((6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (enantiomer 1) (24 mg, 0.03737 mmol) in dimethyl sulfoxide (1 .5 ml). The reaction mixture was placed in an oil bath at 150 "C and allowed to stir overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (gradient 10-99 95 acetonitrile water modified with 0.195 hydrochloric acid), obtaining 11 -IZ3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-17/Ab-thia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15, 8.09,14Hygtricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (compound 251) (9.3 mg, 41 90). IN NMR (400 MHz, DMSO-ab) b 12.45 (5, 1H), 8.20 (a, 9 - 2.8 Hz, 1H), 7.74 (a, 9 - 33.0 Hz, 2H), 7.17 (5, 1H), 6.90 (a, U - 8.2 Hz, 1H), 6.82 (5, 1H), 6.10 (a, 9 - 2.8 Hz, 1H), 4.37 (I, 9U - 6.8 Hz, 2H), 2.25 (5, ЗН), 1.90 (d, U - 6.68 Hz, 4H), 1.56 (5, 6H),

Zo 1.49 (5, 2H), 0.68 (49, U - 13.4, 8.6, 5.0 Hz, 2H), 0.46 - 0.34 (t, 5H), 0.30 (aa, U - 15.8, 8.9, 6.7 Gu, 1H), 0.25 - 0.15 (t, 2H), 0.09 - 0.02 (t, 2H). Two protons are hidden by the solvent. MO-IER t/7 calc. 605.27844, found 606.2 (M.-1)k; retention time: 2.3 min. (Method of RH B).

Example 78: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1Iheptan-7-yl)-2,2-didetero-ethoxy)-1H-pyrazol-1-ylI|-12,12- dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane- 2,2,4-trione (Compound 252) pi «ier2 vir Z zier 4 o zivr5

Same Z. 2 Z "Ve X shi -- X --sh on o ro ro ro ro ro

Yes, yes. schu ХХ ШИ I re zivr8 o (c) (c) r

Uk Me on 7 and ier9 | M ro? 5-4 M SI - r 5-47 M SI x ber M

MN

-- shd-. oh oh oh

And I" o uodya d Zhe Po

Mo 4 po. and 7 sh8-7 r o i udet and shk

Stage 1: dideutero(dispiro(2.0.2.1|heptan-7-yl)umethanol -- z» naya on 5 (c) ro

A solution of ethyl dispiro/2.0.2.1|heptane-7-carboxylate (2.8 g, 16.84 mmol) in tetrahydrofuran (35 mL) was cooled in an ice-water bath. Lithium aluminum deuteride (678 mg, 16.14 mmol) was added in small portions over 3 minutes and the reaction mixture was stirred under nitrogen at ambient temperature for 5 hours. The reaction mixture was cooled in an ice-water bath, the reaction mixture was diluted with ether (40 mL) and slowly quenched by the addition of saturated aqueous Rochelle salt solution (-- 30 mL) until the layers were clearly separated. The lower aqueous layer was extracted with diethyl ether (2 X 30 ml). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to obtain didetero(dispiro(2.0.2.1|heptan-7-ylmethanol) (2.5 g, 98 95) in the form of a light yellow oil. 1H NMR (400 MHz, chloroform-a) 6 4.82 (lat. C, 1 H), 1.62 (s, 1 H), 0.87 (m, 4 H), 0.65-0 ,48 (m, 4 H).

Stage 2: 7-Ibromo(didetero)methylidispiro|2.0.2.1|)heptane ---.- on Vg r (c) r |B)

A solution of bromine (1.1 ml, 21.3 mmol) in dichloromethane (9 ml) was added to a solution of triphenylphosphine (5.3 g, 20.1 mmol) in dichloromethane (74 ml) in a nitrogen atmosphere at -15"C for 15 minutes. The reaction mixture was stirred for another 15 minutes at -15 "С, and then cooled to -30 "С. A solution of didetero(dispiro(2.0.2.1|heptan-7-yl)methanol (2.5 g, 16, 6 mmol) and pyridine (1.65 mL, 20.5 mmol) in dichloromethane (18 mL). The mixture was heated to -5 C, stirred for 1 h and poured into pentane (1 L). The precipitate was filtered and the filtrate was concentrated. pentane (300 mL) was added to the residue, the mixture was sonicated and filtered. The filtrate was concentrated to give a white solid which was again treated with pentane (300 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography using a gradient of 0-5 96 diethyl ether in pentane. Fractions containing the product were combined and concentrated at 300 mbar in a water bath at 30 "C to obtain 7-

From Ibromo(didetero)methylidispiro|2.0.2.1|)heptane (2 g, 58 95) as a white solid. 1N

NMR (250 MHz, chloroform-a) 6 1.88 (s, 1H), 0.8-1.0 (m, 4H), 0.63-0.72 (m, 2H), 0.48- -0.6 (m, 2H).

Stage 3: 2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylacetonitrile

M

Wg de ro, ro,

Sodium cyanide (753 mg, 27.53 mmol) was added to a solution of 7-Ibromo(didetero)methylidispiro|(2.0.2.1)heptane (2.3 g, 22.02 mmol) in dimethyl sulfoxide (30 mL), and the reaction mixture was stirred at at room temperature for 2 hours. The mixture was diluted with saline solution (40 ml) and extracted with pentane (2 x 50 ml). The combined layers of pentane were dried over magnesium sulfate, filtered and concentrated to give 2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylacetonitrile (1.8 g, 77 95) as a colorless oil. 1H NMR (250 MHz, Spiogoitogtt-4) b 1.68 (5, 1H), 0.8-1.05 (t, 4H), 0.65-0.8 (t, 2H), 0.54-0.62 (t, 2H).

Stage 4: 2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylacetic acid. --f-f oh

M do on ro ro 2,2-dideutero-2-dispiro(2.0.2.1|heptan-7-ylacetonitrile (7.7 g, 56.951 mmol) was dissolved in

SNZSmageg (105 ml) at room temperature. Sodium deuteroxide (52.2 g, 40 95 wt., 509.23 mmol) was added, followed by SNZSulaiego (105 ml). The mixture was heated at 72 "C in an oil bath in a nitrogen atmosphere (balloon) for 16 hours. The mixture was cooled in an ice water bath for 15 minutes. 020 (-- 20 ml) was added. To extract the aqueous mixture, ether (2 x 50 ml ). The aqueous layer was saved and treated with hydrochloric acid (6 N) to pH - 2. The mixture was extracted with ether (3 x 50 ml). The combined ether layers were dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 2,2-dideutero -2-dispiro|2.0.2.1|heptan-7-ylacetic acid (b g, 6595) in the form of a pale yellow solid. TN NMR (250 MHz, chloroform-4) b 1.64 (s, 1H), 1 ,01- 0.73 (m, 4H), 0.67 (ddd, y) - 8.3, 4.9, 3.5 Hz, 2H), 0.58-0.35 (m, 2H).

Stage 5: 2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethanol (c) --yes." he he ro, ro

Lithium aluminum hydride (2.84 g, 74.827 mmol) was weighed into a round-bottomed flask and cooled in an ice water bath under a nitrogen atmosphere (balloon). Tetrahydrofuran (150 ml) was added and the mixture was stirred at 0 "C for 10 minutes. Then 2,2-dideutero-2-dispiro(2.0.2.1| heptane-7-ylacetic acid (8.1 g, 52.528 mmol) in tetrahydrofuran solution (20 mL, 10 mL for washing). The mixture was slowly heated to

From room temperature and stirred for 15 hours. Then it was cooled in an ice water bath and slowly quenched with Rochelle's saline solution. Ether (200 mL) was added, the layers were separated, and the aqueous layer was extracted with additional ether (2 x 150 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethanol (7.5 g, 89 95) as a pale yellow oil . "IN NMR (250 MHz, chloroform-4) b 3.62 (s, 2H), 1.69 (s, 1H), 0.73-1.0 (m, 4H), 0.60-0, 75 (m, 2H), 0.45-0.59 (m, 2H).

Stage 6: tert-butyl-3-(2,2-dideutero-2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazole-1-carboxylate

(c) and ХК weight of ore (о) on the 5th тЖща- я ro

To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (10.25 g, 55.65 mmol) and 2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-yl-ethanol ( 8.193 g, 58.43 mmol) in tetrahydrofuran (128.1 ml) was added triphenylphosphine (15.33 g, 58.45 mmol). Diisopropylazodicarboxylate (11.82 g, 58.45 mmol) was slowly added dropwise to the mixture over a period of minutes. The reaction mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was removed under reduced pressure and the residue was purified by chromatography on silica gel using a shallow gradient from 100 95 hexane to 100 95 ethyl acetate to give tert-butyl-3-(2,2-dideutero-2-dispiro|2.0.2.1|heptane-7- ylethoxy)pyrazole-1-carboxylate (11.57 g, 6895) in the form of a transparent syrup. MO-IER t/: calc. 306.19125, found 307.2 (M--1)w; retention time: 0.8 min. (Way

RH A).

Stage 7: 3-(2,2-dideutero-2-dispiro(|2.0.2.1|heptan-7-ylethoxy)-1H-pyrazole

U. in -MN -- What and about (in) vo ro

Tert-butyl-3-(2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1-carboxylate (11.57 g, 37.76 mmol) was dissolved in dichloromethane (115.7 ml ) with trifluoroacetic acid (43.64 ml, 566.4 mmol), and the reaction mixture was stirred at room temperature for 2 hours.

The solvent was evaporated and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous part was extracted two more times with ethyl acetate, then the organic layers were combined, washed with saline solution, dried over sodium sulfate, filtered and evaporated to obtain 3-(2,2-dideutero-2-dispiro(2.0.2.1|Heptane-7- ylethoxy)-1H-pyrazole (7.789 g, 100 95) as an oil. MO-IER t/2 calcd. 206.13881, found 207.1 (Ma1)k; retention time: 0.59 min. (Method RH A ).

Stage 8: tert-butyl-2-chloro-6-I3-(2,2-dideutero-2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylate (c) re ke and I ro, si M SI

Tert-butyl. 2,6-dichloropyridine-3-carboxylate (9.368 g, 37.76 mmol), 3-(2,2-didetero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)-1H-pyrazole (7.789 g, 37.76 mmol) and potassium carbonate (6.268 g, 45.35 mmol) were combined in anhydrous dimethyl sulfoxide (155.8 mL). 1,4-diazabicyclo(2.2.2|octane (848 mg, 7.560 mmol) was added and the mixture was stirred at room temperature in

From a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (300 ml) and stirred for 15 minutes. The solid was filtered off and washed with water. The solid substance was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated to obtain tert-butyl-2-chloro-6-I3-(2,2-didetero-2-dispiro(2.0.2.1|heptan-7-yl-ethoxy) pyrazol-1-yl|pyridine-3-carboxylate (15.54 g, 98 95) as a white solid.

MO-0ER t/» calc. 417.17883, found 418.1 (M--1) same; retention time: 0.97 min. (Method of RH A).

Stage 9: 2-Chloro-6-I3-(2,2-dideutero-2-dispiro(|2.0.2.1|heptan-7-yl-ethoxy)pyrazol-1-yl|pyridin-3-carboxylic acid

(in)

Zhy rym Mi si M -

Tert-Butyl-2-chloro-6-I3-(2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylate (15.54 g , 37.18 g mmol) was dissolved in dichloromethane (155.4 mL) with trifluoroacetic acid (42.97 mL, 557.7 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, ether was added to the formed solid, and then the ether was removed under reduced pressure. This was repeated twice more to give a white solid which was recrystallized from dichloromethane to give the pure product as a solid. The product remained in the filtrate, which was evaporated to give an off-white solid, which was dissolved in ethyl acetate and washed with 5 n. sodium hydroxide (2x), then 1 n. with hydrochloric acid (1x), then dried (sodium sulfate), filtered and concentrated to a white solid, purified by reversed-phase HPLC-MS using a column I IPA C18 (2) (75 x 30 mm, particle size 5 μm) , sold by Rpepotepeh (art.: 00С-4252-00-АХ), and running with a double gradient with mobile phase B 20 95 to 80 95 for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "C) to obtain a pure product, which was combined with the initially crystallized material to obtain 2-chloro-6-| 3-(2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (10.43 g, 78 95) as a white solid. MO-IER t/2 calcd 361.1162, found 362.1 (Ma1) xx, retention time: 0.78 min (RC Method A).

Stage 10: tert-butyl (45)-4-13-C(6-C2-chloro-6-(3-(2,2-didetero-2-dispiro|2.0.2.1|heptan-7-yl-ethoxy) pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate about uk MU oi M

M (o o U Met (c)

To a solution of 2-chloro-6-I3-(2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (2 g, 5.528 mmol) in tetrahydrofuran (13.66 mL) was added carbonyldiimidazole (1.12 g, 6.907 mmol) (freshly recrystallized from tetrahydrofuran), and the mixture was stirred at room temperature for 3 hours. Then tert-butyl (45)-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (2.383 g,

Zo 5.776 mmol) as a solution in tetrahydrofuran (5 mL) and then 1,8-diazabicyclo (5.4.0) undec-7-ene (2.594 mL, 17.35 mmol), and the resulting mixture was stirred for 3 hours at room temperature temperature The reaction mixture was diluted with water and ethyl acetate, and then hydrochloric acid (6.178 ml, 6 M, 37.07 mmol) was added to the aqueous layer (pH - 1). The layers were separated, and the organic layer was washed with water (1X) and brine (1X), then dried over sodium sulfate, filtered and concentrated to a white foam, which was purified on a 275 g C 18 reverse phase column, eluting with a gradient from 50 95 -100 95 acetonitrile/water to obtain tert-butyl-(4 5)-4-IZ3-K6-Ce-chloro-6-(3-(2,2-didetero-2-dispiro|2.0.2.1|heptan-7-ylethoxy) )pyrazol-1-yl|pyridin-

C-Carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (3.0854 g, 74 95) as a white solid. MO-IER Ip/2 calc. 755.32007, found 756.1 (Mat) k; retention time: 0.93 min. (Method of RH A).

Stage 11: 2-chloro-6-I3-(2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-yl-ethoxy)pyrazol-1-yl|-M-(b-

IZ-K(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide zbo

9 o

PU se -8- Y Mo

N s what v o Y Match i se -4 th M - M I sh- Ko --shzhht vro -Y M SI xx o -- Mn u, o TRA NM

Tert-butyl (4 C)-4-3-((6-C2-chloro-6-I3-(2,2-dideutero-2-dispiro(|(2.0.2.1|heptan-7-ylethoxy)pyrazole-1 -yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (3.0854 g, 4.079 mmol) was dissolved in dichloromethane (13.46 mL) and trifluoroacetate was added acid (12.57 mL, 163.2 mmol) and the mixture was stirred at room temperature for 90 min. The mixture was concentrated to dryness under reduced pressure. Toluene (50 mL) was added and the mixture was evaporated on a rotary evaporator (water bath at 45 C). Toluene (50 ml) was added again and removed by rotary evaporation (water bath at 45 "С), then dried in vacuum, obtaining 2-chloro-6-I3-(2,2-dideutero-2-dispiro|2.0.2.1|heptane -7-ylethoxy)pyrazol-1-yl|-M-((6-I3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide ( trifluoroacetate salt) (3.142 g, 100 95) as a white solid. MO-IER t/2 calcd. 655.26764, found 656.2 (M--1) k; retention time: 0.65 min. (Method RH A).

Stage 12: (145)-8-I3-(2-nd (dispiro(2.0.2.1|heptan-7-yl)-2,2-didetero-ethoxy)-1H-pyrazol-1-yl|- 12, 12-dimethyl-2A6-thia-3,9,11,18,23-pentaaztetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane -2,2,4-trione (Compound 252) (9) p; (c) o o

V Y y y n- r I MU si M / | and IF at 5 Mo. r and shl-x ro? HER M M h

MN shd-3

MN and it sucks

To a solution of 2-chloro-6-I3-(2,2-dideutero-2-dispiro(2.0.2.1)heptan-7-ylethoxy)pyrazol-1-yl|-M-((6-

13-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetate salt) (3.142 g, 4.079 mmol) in MMR (188.5 mL) was added potassium carbonate (3.946 g, 28.55 mmol). The mixture was purged with nitrogen for 5 min. The mixture was heated at 150 °C for 24 h. The reaction mixture was cooled to room temperature and added to water (-200 mL) to give an off-white solid. The mixture was carefully acidified with hydrochloric acid (6.798 mL 6 M, 40.79 mmol), yielding a foamy suspension. The solid was collected by filtration, and the wet filtered precipitate was dissolved in ethyl acetate and washed with brine(s) and a little b.n. hydrochloric acid to keep the layers clear. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give a light yellow oil, which was chromatographed on a reversed-phase column with 275 g of C18, eluting with a mixture of 550-100 90 acetonitrile/water, to obtain (145)-8-I3-(2-

Zoidispiro(2.0.2.1|)heptan-7-yl)-2,2-dideteroethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia- 3,9,11,18,23 -pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (Compound 252) (2.16 g , 85 95) in the form of a white solid. TN NMR (400 MHz,

DdMSO-ab) b 12.50 (5, 1H), 8.20 (y, U - 2.8 Hu, 1H), 7.81 (y, 9 - 8.2 Hz, 1H), 7.58 (aa, U - 8.5, 7.2 Hz, 1H), 7.05 (a, U - 7.1 Hz, 1H), 6.98 (a, U - 8.7 Gu, 1H), 6.91 (a, U - 8.2 Hz, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.08 ( a, 9 - 2.7 Hz, 1H), 4.20 (a, 9 - 1.4 Hz, 2H), 3.92 (a, U - 12.9 Hz, 1H), 3.17 (a, U - 5.0 Hz, 1H), 2.95 (y, U - 13.1 Hz, 1H), 2.69 (y, U - 13.8 Hz, 1H), 2.13 (5, 1H), 1.86 (aa, U - 11.6, 5.2 Hz, 1H), 1.77 (5, 1H), 1.59 ( a, 9 - 7.7 Hz, 6Н), 1.51 (5, ЗН), 1.46 (в, 1Н), 1.38 - 1.24 (t, 1Н), 0.83 (5, 4Н), 0.69 - 0.60 (t, 2Н), 0.55 - 0.44 (t, 2H). MO-IER t/2 calc. 619.29095, found 620.2 (Ma1)k; Holding time: 2.37 min. (Method of RH B).

Example 79: Preparation of (145)-8-(3-2-|(7-deuterium)dispiro(|2.0.2.1|heptan-7-yl|utoxy)-1H-pyrazol-1-yl)-12,12 -dimethyl-2A6-thia-3,9,11,18,23-

pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 253)

M (9) oh 5ier 1 r

M n ziver2 r 5ier Z i z -3 -- zla z on z shchi (c) and M. vir 4 zier 5 r o o zir 6 o zier 7 on on -:

GT (9)

M

/ р ра (c) 7 kn Ж 0-07 M 9) weaver 8 more hu o -- ---» р я | Vier 9 r and r; -06--OO

SI M SI

(9)

In school o and Mn 60205020 (o (in 9 o

We (in) o - (8) xx her to s ih

Mu - M | 5 Ier 12 | H -O0 0-0 M Go xx M ru I o - -0- 5-7 MO M

Mn or dd- o A y, (c)

Stage 1: ethyl 7-deuterodispiro(2.0.2.1Heptane-7-carboxylate (c)

M r

M TK I -- ------ Gee! c) --t r o

A solution of cyclopropylidenecyclopropane (5.3 g, 66.1 mmol) in dichloromethane (15 mL) was cooled in an ice water bath. Rhodium (II) acetate dimer (600 mg, 5.2038 mmol) was added in one portion. The mixture was stirred in a nitrogen atmosphere at 0-57C for 5 minutes. Then, ethyl 2-deuterium-2-diazoacetate (20 mL, 152 mmol), obtained according to CHAS5, 1993, 115, 2239, was added using a syringe pump at a rate of 0.11 mL/h.

The addition lasted 26 hours. After completion of the addition, the mixture was stirred for another 10 min. The mixture was concentrated to a volume of 50 ml and filtered through a layer of silica gel. The pad was washed with dichloromethane (200 ml), and the combined filtrate was concentrated to a volume of 50 ml, filtered again and washed with dichloromethane (300 ml). The filtrate was concentrated to obtain ethyl 7-deuteriodispiro(2.0.2.1|)heptane-7-carboxylate (9 g, 66.25 95) as a light yellow oil. 1N

NMR (250 MHz, chloroform-a) b 4.13 (q, U - 7.1 Hz, 2H), 1.39-1.14 (m, 4H), 1.11-0.92 (m, ЗН ), 0.91-0.67 (m, 4H).

Stage 2: (7-deuteriodispiro(|2.0.2.1|heptan-7-yl) methanol p r ---zhzephal ne on (c)

A solution of ethyl 7-deuteriodispiro(2.0.2.1|1heptane-/-carboxylate (9 g, 53.82 mmol) in tetrahydrofuran (100 mL) was cooled in an ice-water bath. Lithium aluminum hydride (2.5 g, 65.78 mmol) was added in small portions over 5 min and the mixture was stirred under nitrogen at ambient temperature for 5 h. The reaction mixture was cooled in an ice-water bath for 5 min, diluted with ether (200 mL) and slowly quenched by addition of a saturated aqueous Rochelle salt solution (ca. 30 mL) until the layers were clearly separated. The aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined ether layers were washed with brine (50 mL), dried over magnesium sulfate, and concentrated to give (7- deuteriodispiro(2.0.2.1|heptan-7-ylmethanol (4.7 g, 98 95) in the form of a light yellow oil. TN NMR (250 MHz, chloroform-a) b 3.72 (s, 2H), 1.00 -0.75 (m,

AN), 0.74-0.44 (m, 4Н).

Stage 3: 7-(bromomethyl)-7-deuteriodispiro(2.0.2.1|)heptane p -- EE-z» p on Vg

A solution of triphenylphosphine (9.38 g, 35.65 mmol) in dichloromethane (130 mL) under a nitrogen atmosphere was cooled to -15 °C using an acetone bath with dry ice. A solution of bromine (1.85 mL, 35.65 mmol) in dichloromethane (17 ml) was added over 15 minutes, and the reaction mixture was stirred for another 15 minutes at -15"C. The mixture was cooled to -30°C and a solution of (7-deuteriodispiro|2.0.2.1|heptan-7-yl)methanol (4.5 g, 35.95 mmol) and pyridine (2.9 mL, 36 mmol) in dichloromethane ( 34 ml) was added dropwise. Then the mixture was heated to -5 "C and stirred for 1 hour. The reaction mixture was poured into pentane (1 L), resulting in the formation of a white precipitate. The solid was filtered through celite and the filtrate was concentrated (250 mbar with a water bath at about 30°C) to give a white solid. Pentane (300 mL) was added, the mixture was sonicated and filtered. The filtrate was concentrated to give a white solid, which was treated again with pentane. (300 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography using 0-5 95 diethyl ether in pentane. Fractions containing the product were concentrated at 300 mbar in a water bath at 30 C to give 7-( bromomethyl)-7-deuteriodispiro(2.0.2.1|heptane (6.4 g, 95 95) in the form of a clear oil. NMR (250 MHz, chloroform-a) b 3.49 (s, 2H), 1.42- 1.17 (m, 2H),

From 1.12-0.81 (m, 2H), 0.79-0.64 (m, 2H), 0.62-0.43 (m, 2H).

Stage 4: 2-(7-deuteriodispiro|2.0.2.1|heptane-7-ylluacetonitrile

X|c) - same r

Vg vk.

Sodium cyanide (753 mg, 27.53 mmol) was added to a solution of 7-(bromomethyl)-7-deuteriodispiro(2.0.2.1|)heptane (2.3 g, 22.02 mmol) in dimethyl sulfoxide (30 mL) and the reaction mixture stirred at room temperature for 2 hours. The mixture was diluted with saline solution (40 ml) and extracted with pentane (2 x 50 ml). The combined pentane layer was dried over magnesium sulfate, filtered and concentrated to give 2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl)acetonitrile (4 g, 87 905) as a clear oil. 1H NMR (250

MHz, chloroform-4) 5 2.42 (s, 2H), 1.04-0.79 (m, 4H), 0.79-0.65 (m, 2H), 0.65--0.44 (m, 2H).

Step 5: 2-(7-deuteriodispiro(2.0.2.1|heptan-7-yl)/acetic acid

X and M ------ ro on

A solution of sodium hydroxide (12 g, 300 mmol) in water (25 ml), and the resulting solution was stirred at 73 "C for 15 hours. The mixture was cooled to room temperature, diluted with water (-40 ml) and extracted with diethyl ether (2 x 25 ml). The aqueous phase was adjusted to pH - 1 by adding 6 M hydrogen chloride acid and then extracted with diethyl ether (2 x 40 mL).The combined ether layers were dried over magnesium sulfate, filtered and concentrated to give 2-(7-deuteriodispiro(2.0.2.1|heptan-7-yl)acetic acid (2, 6 g, 57 95) as a slightly yellow solid. 1H NMR (250 MHz, chloroform-4) 5 2.44 (s, 2H), 1.03-0.73 (m, 4H), 0.75- 0.61 (m, 2H), 0.59-0.38 (m, 2H).

Stage 6: 2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl)ethanol r. o - n- V r on on

A suspension of lithium aluminum hydride (836 mg, 22 mmol) in tetrahydrofuran (35 mL) was cooled in an ice water bath. 2-(7-Deuteriodispiro(2.0.2.1|heptan-7-yl)acetic acid (2.59 g, 16.9 mmol) in tetrahydrofuran (15 mL) was added dropwise over 10 min. The mixture was allowed to warm to ambient temperature and stirred under nitrogen for 15 h.The reaction mixture was cooled in an ice-water bath for 5 min, then diluted with diethyl ether (60 mL) and slowly quenched by addition of saturated aqueous Rochelle salt solution (x 40 mL) until the layers were not clearly separated. The lower aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined ether layers were washed with brine (40 mL), dried over magnesium sulfate, filtered, and concentrated to give 2-(7-deuteriodispiro|2.0). 2.1|heptan-7-yl) ethanol (2.4 g, quantitative yield) in the form of a light yellow oil. IN NMR (250 MHz, chloroform-a) b 3.63 (t, U - 6.9 Hz, 2H ), 1.68 (t, U - 6.8 Hz, 2H), 0.94-0.72 (m, 4H), 0.72-0.57 (m, 2H), 0.57-0, 38 (m, 2H).

Stage 7: tert-butyl-3-(2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl) ethoxy|pyrazole-1-carboxylate (c) x ura M re ris

Ho - or t nM--m o d- on o-

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (1.26 g, 6.84 mmol) and 2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl)ethanol (1 g , 6.48 mmol), triphenylphosphine (1.78 g, 6.8 mmol) in tetrahydrofuran (10 ml) was added dropwise diisopropyl azodicarboxylate (1.34 ml,

Zo 1.18 mmol) and the reaction mixture was stirred at 50 "C for 12 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography using a gradient from 10095 hexane to 1095 ethyl acetate in hexane to give tert-butyl-3-( 7-deuteriodispiro(2.0.2.1|)heptan-7-yl)umethoxy|pyrazole-1-carboxylate (1.75 g, 80 95) as a white solid. 1H NMR (250 MHz, Spiogoitogit-4) b 7.82 ( y, y - 2.9 Hz, 1H), 5.84 (a, 9 - 3.0 Hz, 1H), 4.26 (5, 2H), 1.58 (5, 9H), 1.44 (a, 9 - 6.2 Hz, 2H), 0.93 - 0.73 (t, 4H), 0.65 (y, U - 9.2 Hz, 2H), 0.49 (a, U - 8.68 Hz, 2H). MO-IER t/2 calculated 306.2, found 307.3 (M--1); Retention time: 4.85 min (method RH R).

Stage 8: 3-(2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl)ethoxy|-1H-pyrazole

M re ra 5-4 -a - - same zv z Y V

Trifluoroacetic acid ( 10 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL ). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to obtain 3-| quantitative yield) . in the form of a white solid. TN NMR (250 MHz,

SNiogotogite-a) b 7.35 (y, U - 1.3 Hz, 1H), 5.71 (a, 9 - 1.4 Hz, 1H), 4.12, 9 - 7.8 Hz, 2H), 1.87 1.9 - 6.7 Hz, 2H), 0.96 - 0.73 (t, 4H), 0.70 - 0.58 (t, 2H), 0.56 - 0.39 (t, 2H). MO-IER tp/2 calc. 205.1, found 206.4 (M--1)k; Holding time: 2.95 min. (The method of RH R).

Stage 9: tert-butyl. 2-chloro-6-I3-(2-(7-deuteriodispiro(2.0.2.1)heptan-7-yl)ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylate (6)

M o 5 Uk - Z M uva o / -/ | y5 (c) zhk V m si r v; and --

SI M SI

To a mixture of tert-butyl-2,6-dichloropyridine-3-carboxylate (1.44 g, 5.mmol) and 3-(7-deuteriodispiro(2.0.2.1|)heptan-7-yl)umethoxy|-1H-pyrazole (1.2 g, 3.93 mmol) in anhydrous dimethylsulfoxide (24 ml) was added potassium carbonate (965 mg, 6.97 mmol) and 1,4-diazabicyclo(|2.2.2|octane (130 mg, 1.16 The resulting mixture was stirred under nitrogen at room temperature for 16 h. The mixture was then diluted with water (45 mL) and stirred for 15 min. The resulting white solid was collected by filtration and washed with water (2 x 20 mL). The solid was dried and purified by silica gel column chromatography using a gradient from 100 95 hexanes to 60 95 ethyl acetate in hexane to give tert-butyl-2-chloro-6-(3-((7-deuteriodispiro|2.0.2.1|heptan-7-yl )umethoxy|pyrazol-1-yl|pyridine-3-carboxylate (1.8 g, quantitative yield) as a white solid. 1H NMR (250

MHz, Spiogoitogit-4) b 8.34 (aa, U - 2.9, 1.1 Hu, 1H), 8.18 (ai, 9 - 8.4, 1.1 Hz, 1H), 7.69 (ai, y - 8.4, 1.0 Gu, 1H), 5.93 (aa, U - 2.9, 1.1 Hz, 1H), 4.24 (5, 2H), 1.74 - 1.52 (t, 10OH), 1.48 (5,1H), 0.93 - 0.77 (t, 4H), 0.71 - 0.60 (t , 2H), 0.55 - 0.44 (t, 2H). MO-IER tp/: calc. 416.2, found 417.5 (М--1) k;

Holding time: 4.87 min. (The method of RH R).

Zo Stage 10: 2-chloro-6-I3-(2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl)ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (c) (c) 5-47 cha si -U- 5-47) We sy r ry r You

To a solution of tert-butyl-2-chloro-6-I3-(7-deuteriodispiro(|2.0.2.1|)heptan-7-yl) methoxy| pyrazol-1-yl|pyridine-3-carboxylate (1.8 g, 4.32 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 15 hours.

The mixture was concentrated, and the residue was triturated with a mixture of diethyl ether/pentane (20 mL each). The precipitated solid was collected by filtration to give 2-chloro-6-I3-((7-deuteriodispiro|2.0.2.1|heptan-7-ylmethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (1.19 g, yield 76 95) as a white solid. 1H NMR (250 MHz, DMSO-46) b 8.46 - 8.34 (t, 2H), 7.72 (ad, 9 - 8.4, 0.8 Hz, 1H), 6.17 (aa, U - 2.9 , 0.8 Hz, 1H), 4.23 (5, 2H), 1.46 (5, 2H), 0.92 - 0.74 (t,

AN), 0.64 (aa, y - 7.6, 4.3 Hz, 2H), 0.50 (49, 9U - 7.1, 4.2 Hz, 2H). MO-IER t/2 calc. 361.1, found 361.3 (M--1) k; retention time: 3.85 min. (The method of RH R).

Stage 11: tert-butyl (4S)-4-3-(6-C2-chloro-6-I3-(2-(7-deuteriodispiro|2.0.2.1|)heptan-7-yl ethoxy|pyrazol-1-yl| Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl- pyrrolidine-1-carboxylate (c)

A MN -Щ- same o--IM M si xx

And 9 and a Mn with. ; (at)

To a solution of 2-chloro-6-I3-(2-(7-deuteriodispiro|2.0.2.1|heptan-7-yl)ethoxy|pyrazol-1-yl|pyridin-

C-carboxylic acid (100 mg, 0.2772 mmol) in tetrahydrofuran (2 ml) was added carbonyldiimidazole (54 mg, 0.3330 mmol) and the mixture was stirred under nitrogen atmosphere (balloon) at room temperature for 2 hours. Then tert-butyl (45)-2,2-dimethyl-4-I(3-|((6-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-i-carboxylate) (121 mg, 0.2933 mmol) was added followed by the addition of 1,8-diazabicyclo(/5.4.FOundec-7-ene (130 μL, 0.8693 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride/saline solution 1:1 The organic phases were separated, dried over sodium sulfate, filtered, and evaporated. 6-Ce-chloro-6-I(3-(2-(7- deuteriodispiro|2.0.2.1|heptan-7-yl)ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridylyamino |Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (77 mg, 31 95) as a white solid. MO-IER t/2 calcd. 754.3138, found 755.46 (Ma1)-; retention time: 0.67 min (Method RH C).

Stage 12: (145)-8-(3-2-((7-deuterium)dispiro(2.0.2.1|heptan-7-yl|ethoxy)-1H-pyrazol-1-yl)-12,12-dimethyl -2A6-thia-3,9,11,18,23-pentaaztetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2, 2,4-trione (Compound 253) (c)

Ho (in) o o C to he Ya

M - cha | N t r - -.Y M M xx

MN o d- A (o) MN co U veins I (c)

Coo)

Solution of tert-butyl (45)-4-I3-((6-Ce-chloro-6-|3-(2-(7-deuteriodispiro(2.0.2.1|heptan-7-yl ethoxy|pyrazol-1-yl|Ipyridine -3-carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-i-carboxylate (77 mg, 0.1019 mmol) in dichloromethane (400 μl) and trifluoroacetic acid (100 μl, 1.307 mmol) were stirred at room temperature for 4 hours. The solvents were removed by evaporation, and the resulting residue was dissolved in ethyl acetate. It was washed with 2 mL of saturated sodium bicarbonate solution, the organic layer was collected, and the solvent was evaporated. The resulting thick oil was further dried in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (5 mL), molecular sieves Z A were added and the reaction mixture was stirred for 10 min. Then cesium fluoride (49 mg, 0.3226 mmol) and potassium carbonate (47 mg, 0.3401 mmol) were added, and the reaction mixture was heated at 150 °C for 16 hours .

The reaction mixture was filtered through a UUpaytap disc filter (Rigadies 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 50-

99 95 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain (145)-8-(3-(2-((7-deuterium )dispiro|2.0.2.1|heptan-7-yl|ethoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!yl17.3.1 .111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 253) (26.9 mg, 43 95) in in the form of a white solid. 1H NMR (400 MHz, Spiogothogite-4) b 8.18 (a, Y - 2.8 Hz, 1H), 8.05 (a, Y - 8.3 Hz, 1H), 7.58 - 7.47 (t, 2H), 7.26 (5, 1H), 6.56 (0.9 - 8.2 Hz, 1H), 5.89 (y, U - 2.8 Hz, 1H), 4.71 (5, 1H), 4.24 (I, U - 6.8 Hz, 2H), 3.85 (y, U - 37.1 Hz, 1H), 3.32 (5, 1H), 3.15 (y, 9 - 13.6 Hz, 1H), 3.02 (y, 9 - 27.68 Gu, 1H), 2.56 (5, 1H), 2.06 (I, U - 10.0 Hz, 1H), 1.89 (i,

U 6.68 Hu, 2H), 1.74 - 1.37 (t, 10OH), 0.85 (d, U - 2.4 Hz, 4H), 0.75 - 0.58 (t, 2H), 0.55 - 0.42 (t, 2H).

MO-0ER t/» calc. 618.2847, found 619.15 (M--1)f; Holding time: 1.96 min. (Method RK 5).

Example 80: Preparation of (145)-8-I(3-(2-I6dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-20-hydroxy-12,12-dimethyl- 2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4- trion (compound 254) on

Beh still GT 4 5iver 1 5

SSO no rr, Zhe she shchi and Mo in Ve M mo, and DI tu with M mo, o H M mo, -- -yu t o s KA he shcha o. H M Mn, 9) ko M E --k (9) (9) 98 and mn, d o. with

DI Eh Fe x M | - th zier8 o x vier 7 on M m Mn 0-th m M SI

From February to August

Z. M. E

PA Fr

Vos--m ve "Zh o o | fa re y Mn y: m " her uv X zivr9 m so Ge) sverto o o, o

From U on

OO oo t- a | hu her 5 and M zier 11 0-7 c)

Stage 1: 3-benzyloxy-6-bromo-2-nitropyridine on som. Note 2

Vg M Mo, y, Vi 2 mo,

A solution of 6-bromo-2-nitropyridin-3-ol (12 g, 54.796 mmol) in dry M,M-dimethylformamide (100 mL) under nitrogen was cooled in an ice water bath. Sodium hydride (2.49 g, 62.256 mmol, 6095 in mineral oil) was added in one portion and the reaction mixture was stirred for 10 minutes. Benzyl chloride (7.5900 g, 6.9 mL, 59.961 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at 60 "C for two days. The reaction mixture was allowed to cool to room temperature, quenched with water (200 mL) and extracted with ethyl acetate (5 x 100 mL). The combined organic layers were washed with brine (3 x 70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated in a mixture of heptanes/ethyl acetate 4:1 (50 mL). The resulting solid was filtered, washed with heptane and dried under reduced pressure to give 3-benzyloxy-6-bromo- 2-nitropyridine (13.643 g, 81 95) as a yellow solid. TN NMR (300 MGu, SOSIS) b 5.23 (5, 2H), 7.33-7.43 (t, 6H), 7.60 (a, U - 8.7 Hu , 1H). MO-IER t/2 calculated 307.9797, found 309.0 (Ma1) k;

Holding time: 2.155 min. (Method РХ 1).

Stage 2: 2-Ethylhexyl 3-((5-benzyloxy-6-nitro-2-pyridyl)sulfanyl|propanoate (o) obliquely (c) Zn t yavy MI sko, pu M sko,

To a degassed solution of 3-benzyloxy-6-bromo-2-nitropyridine (13.143 g, 42.518 mmol) and diisopropylethylamine (11.130 g, 15 mL, 86.117 mmol) in dry toluene (260 mL) was added xanthophos (1.49 g, 2, 5751 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.155 g, 1.2613 mmol) and diisopropylethylamine (11.130 g, 15 mL, 86.117 mmol). The reaction mixture was refluxed and stirred overnight at 110 "C. The reaction mixture was cooled to room temperature, filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel. The companion was loaded with heptane (gradient from 10095 heptane to 30905 ethyl acetate in heptane) to give 2-ethylhexyl-3-(5-benzyloxy-6b-nitro-2-pyridyl)sulfanyl|Ipropanoate (18.977 g, 95 95). MSO-IER t/2 calcd. 446.1875, found 447, 2 (M.-1)x; retention time: 2.262 min. (Method

РХ и).

Step 3: 2-ethylhexyl 3-((5-benzyloxy-6-nitro-2-pyridyl)sulfonyl|propanoate and co. co

IF

Yes, M mo, Ai uh M mo,

WHAT?

Koo) o

M-chloroperbenzoic acid (19.795 g, 88.326 mmol) was added portionwise to a solution of 2-ethylhexyl-3-(5-benzyloxy-b-nitro-2-pyridyl)sulfanyl|ipropanoate (19.65 g, 44.003 mmol) in dichloromethane (170 ml). The reaction was exothermic and the substance became cloudy. The reaction was stirred overnight at room temperature. Ethyl acetate (200 mL) was added, and the reaction mixture was washed successively with an aqueous sodium bicarbonate solution (200 mL) and 0.5

M aqueous solution of sodium hydroxide (2 x 200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-ethylhexyl-3-|(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl|Ipropanoate (20.905 g, 99 95) as a yellow oil. . 1

NMR (300 MHz, SOSIZ) b 0.83-0.94 (t, 6H), 1.22-1.32 (t, 6H), 1.50-1.64 (t, 2H), 2.87 (I, 9-7.6 Gu, 2H), 3.70 (, 9-7.6 Hu, 2H), 4.01 (da, 9-6.0, 2.2 Hu, 2H), 5.37 (5, 2H), 7.35-7.48 (t, 5H), 7.69 (a, 5-8.5 Hz, 1), 8.22 (y, 9-8.5 Hz, 1H). MO-IER t/2 calc. 478.1774, revealed 367.1 (M-

Сс8НИ161) residential building; retention time: 2.419 min. (Method RH I).

Stage 4: 2-ethylhexyl 3-((6β-amino-5-benzyloxy-2-pyridyl)/sulfonyl|propanoate

MK -- Kh

I and U

To a solution of 2-ethylhexyl-3-(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl|Ipropanoate (6.24 g, 13.039 mmol) in ethanol (250 mL) and water (50 mL) was added iron (2.525 g , 45.214 mmol) and ammonium chloride (2.021 g, 37.782 mmol). The reaction mixture was stirred at 100 "C for 1.5 h, cooled to room temperature, filtered through celite and washed with dichloromethane (200 ml). The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 ml) and washed with water (2 x 50 ml) The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-ethylhexyl-3-(b-amino-5-benzyloxy-2-pyridyl)sulfonyl|propanoate (6.25 g, quantitative yield) in in the form of a yellow oil. MO-IER t/7 calc. 448.2032, found 449.3 (Ma), retention time: 2.565 min. (Method RH M).

Stage 5: 2-ethylhexyl 3-((5-benzyloxy-6-fluoro-2-pyridyl)sulfonyl|Ipropanoate

I and U

A solution of 2-ethylhexyl-3-|(b-amino-5o-benzyloxy-2-pyridyl)sulfonyl|ipropanoate (6.25 g, 13.933 mmol) in hydrogen fluoride in pyridine (71.500 g, 65 mL, 721.45 mmol) cooled to -40 "C. The resulting red solution was treated with sodium nitrite (1.92 g, 27.828 mmol) and allowed to warm to room temperature. Gas evolution was observed and the reaction became orange and cloudy. The reaction mixture was stirred overnight at room temperature and slowly poured onto ice and water (400 mL). The mixture was neutralized by careful addition of aqueous sodium bicarbonate and extracted with ethyl acetate (4 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was flash purified - chromatography on silica gel loaded with heptane (gradient from 100 95 heptane to 4095 ethyl acetate in heptane) to give 2-ethylhexyl-3-((5-benzyloxy-6-fluoro-2-pyridyl)usulfonyl|propanoate (3.691 g, 5995 ) in the form of a yellow oil. MO-IER t/2 calc. 451.1829, found 452.2 (Ma1)zhk; retention time: 2.648 min. (Method РХ 0).

Stage 6: 5-benzyloxy-6-fluoropyridine-2-sulfonamide (6) xx XA B Chi (c)

AH. and IX shchi x y - x r (9) Z M E E sha xx (c) (9)

1,8-diazabicyclo(5 ,4,0)undec-7-ene (2.0200 g, 2 mL, 13.269 mmol). The reaction mixture was stirred for 1 h at room temperature and a solution of hydroxylamine-O-sulfonic acid (3.873 g, 34.246 mmol) and acetate was added of sodium (2.246 g, 27.379 mmol) in water (12 mL). The reaction mixture was stirred for 1 h at room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine ( 30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel loaded with heptane (gradient heptane/ethyl acetate from 1000 to 50:50) to give 5-benzyloxy-6- fluoropyridine-2-sulfonamide (1.58 g, 80 95) as a white solid. TN NMR (300 MHz, DMSO-ab) 6 5.33 (5, 2H), 7.34-7.52 (t, 7H), 7.79-7.95 (t, 2H). 19E NMR (282 MHz, dimethylsulfoxide-ab) 5 - 83.6 (d, U - 12.2 Hz, 1). MO-IER t/: calc. 282.0474, found 283.1 (M--1)k; retention time: 2.33 min. (The method of RH N).

Stage 7: tert-butyl (45)-4-IZ3-K(3-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethyl-pyrrolidine-1-carboxylate

98 x m y xx (c) nd M MN z | r i c)

Vos -M on ME (c)

Vos --ym4

5-benzyloxy- 6-Fluoropyridine-2-sulfonamide (221 mg, 0.7829 mmol) and N,M-diisopropylethylamine (200 μl, 1.148 mmol) in the indicated order under a nitrogen atmosphere. The obtained yellow solution was stirred at 85 "C for 9 hours, then at 40 "C for 13 hours. The reaction mixture was allowed to cool to ambient temperature, ethyl acetate (60 mL) and water (50 mL) were added. Then the solution was acidified with 10 95 citric acid (10 ml) and the layers were separated.

The organic phase was washed with saline solution (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow viscous material. The crude reaction mixture was purified by chromatography on silica gel (40 g of silica gel, eluting with a gradient of 10-60 96 ethyl acetate in hexane for 30 min) to obtain the desired tert-butyl (45)-4-3-((3-benzyloxy-6 -sulfamoyl-2-pyridyl)amino|propyl|- 2,2-dimethylpyrrolidine-1-carboxylate (370 mg, 91 95) as a white foam. MSO-IER t/2 calcd. 518.2563, found 519.4 ( M--1) k; retention time: 1.75 min (Method RH B).

Stage 8: tert-butyl (45)-4-3-(3-benzyloxy-6-|(2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1- yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate and another (9) di

Hm MN a on o o S nah, - dev se H ra - shk kA

Vos -ikM, o

To a stirred solution of /2-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (150 mg, 0.4169 mmol) in to anhydrous tetrahydrofuran (3 mL) was added carbonyldiimidazole (75 mg, 0.4625 mmol) and stirring was continued at ambient temperature under nitrogen for 2 h. A solution of tert-butyl (45)-4-3-(3-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (196 mg, 0.3779 mmol) in anhydrous tetrahydrofuran (1 mL), then 1,8-diazabicyclo/5.4.O1undec-7-ene (220 μL, 1.471 mmol) and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (20 mL) and water (10 mL), and the mixture was slowly acidified with hydrochloric acid (1.6 mL, 1.0 M, 1.600 mmol) to approximately pH 4.0.

The layers were separated and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organic phases were washed with saline (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (24 g silica gel column, gradient 0-70 95 ethyl acetate in hexane over 35 minutes) to give tert-butyl (45)-4-3-((3-benzyloxy-b6-Ce- chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridylIamino|Ipropyl|-2,2-dimethylpyrrolidine- i-carboxylate (171 mg, 3795) as a white solid. MO-IER t/2 calcd. 859.34937, found 860.5 (M--1) k; retention time: 2.49 min. (RC method b).

Stage 9: M-(5-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I3-( 2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) ос КК - о о о о

X m Mn X m MN shcha: p: 5-4 MA ts -6005 5-47 M cho s -- Vos-ki s sh ТРА nm,

To the stirred solution tert-butyl (45)-4-I3-(3-benzyloxy-6-((2-chloro-6-I(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol- 1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (75 mg, 0.08716 mmol) in anhydrous methylene chloride (3 ml) was added trifluoroacetic acid (350 µL, 4.543 mmol) at ambient temperature under nitrogen. The orange solution was stirred for 1 h, then the volatiles were removed under reduced pressure. Toluene (20 mL) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and, finally, dried in a vacuum for 2 hours to obtain crude / M-(5-benzyloxy-6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl |-2-Chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide (trifluoroacetate salt) (66 mg, 8795) The material was transferred directly to the next stage without additional cleaning. MO-IER t/2 calc. 759.29694, found 760.5 (M.-1) same; retention time: 1.43 min. (Method of RH B).

Stage 10: (145)-20-(benzyloxy)-8-13-(2-yldispiro(2.0.2.1|heptan-7-ilyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6 -thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione d ve

Y UF Io no | H M 5 and 2

A 20 ml vial was loaded with M-((5-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2-chloro-6 -I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (60 mg, 0.06862 mmol), potassium carbonate (60 mg, 0 .4341 mmol), cesium fluoride (21 mg, 0.1382 mmol) and anhydrous dimethylsulfoxide (4 ml) in the indicated order. The vessel was purged with a stream of nitrogen for 2 minutes, closed with a lid and stirred at 160 "C for 15 hours. The reaction mixture was given allowed to cool to ambient temperature, and the heterogeneous mixture was diluted with ethyl acetate (30 mL) and water (20 mL) and acidified with hydrochloric acid (1.0 mL, 1.0 M, 1.000 mmol).

The solution was separated and the aqueous layer was extracted with additional ethyl acetate (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by chromatography on silica gel (0 90-10 906 methanol in dichloromethane for 30 min) to give (145)-20-(benzyloxy)-8-I3-(2-ydispiro(2.0.2.1|heptane-7 -yl)ethoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl-2А6-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1( 23),5,7,9,19,21-hexane-2,2,4-trione (41 mg, 83 95) as a white solid. MO-IER t/7 calc. 723.3203, found 724.5 (M--1) k; retention time: 2.27 min. (method RH b).

Stage (11: (145)-8-I3-(2-idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-20-hydroxy-12,12-dimethyl- 2A6-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4- trione (compound 254)

(Yi oi schi I yi B schi on

M s Mn --yaya uk M M Mn for M du Ya du

To a stirred solution (145)-20-(benzyloxy)-8-I3-(2-yIdispiro(2.0.2.1|heptan-7-ylylethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6- thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (30 mg, 0.04144 mmol) in anhydrous methanol (6 mL) was added 10 95 Ra on charcoal (wet, Oedivza) (16 mg, 0.01503 mmol) under a nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (from a cylinder) for 2.5 hours at ambient temperature. The hydrogen cylinder was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethylsulfoxide (1.5 mL) and filtered through a disc filter for a M/paytap syringe with

PTFE 0.45 μm. The sample was purified using a preparative reversed-phase HPLC-MS (column I ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art.: 00С-4252-Ц00-АЧ), (run with by a double gradient from 30 90 to 99 95 acetonitrile in water for 15 min (without modifier) to obtain (145)-8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazole -1-yl1-20-hydroxy-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose-1(23),5, 7,9,19,21-hexane-2,2,4-trione (compound 254) (20 mg, 75 95) as a pale blue-green solid. 1H NMR (400 MHz, Meipapo!- a4) b 8.24 (a, 9 - 2.8 Hu, 1H), 7.82 (a, 9 - 8.3 Hz, 1H), 7.19 (a, y - 7.8 Hz, 1H), 6.97 ( a, U - 8.3 Hu, 1H), 6.89 (9, U - 7.8 Hz, 1H), 5.94 (y, 9 - 2.7 Hu, 1H), 4.24 (I, U - 6.6 Hz, 2H), 4.04 (1, 9 - 13.2 Hz, 1H), 3.37 - 3.32 (t, 1H), 3.14 (ai, 9 - 13.6, 4.4 Hz, 1H), 2.86 (I, U - 10.4 Gu, 1H), 2.30 - 2.13 (t, 1H ), 1.88 (a, U - 6.7 Hz, 4H), 1.78 - 1.66 (t, 2H), 1.66 (v, ЗН), 1.63 - 1.60 (t, 1Н), 1.60 (5, ЗН), 1.48 (Ii, In - 6.6

Gu, 1H), 1.44 - 1.33 (t, 1H), 0.92 - 0.78 (t, 4H), 0.66 (aa, 9 - 8.7, 4.6, 3.3 Hz, 2H), 0.56 - 0.47 (t, 2H). MO-IER t/ calc. 633.2733, found 634.4 (M'-1) k; retention time: 1.9 min. (method RH b).

Example 81: Preparation of (145)-20-hydroxy-12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 255) ye5 on 5-X o

ON your fan 1

EE o ul M Gei) Y y mn - ii uh, ch o.

M so ZU zivr2 where I MN -9 -O. p om o om ZA MU he u. attention | ru N M ts -5; era vv 5-4 ME ed

EE 0th. m y it d- har tuyu

Coo)

Stage 1: tert-butyl (45)-4-I3-((3-benzyloxy-6-C2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine -3-carbonyl|sulfamoyl|-2-pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

To a stirred solution of 2-chloro-6-I3-I(3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (150 mg, 0.3849 mmol) in anhydrous tetrahydrofuran (Z mL) was added carbonyldiimidazole (68 mg, 0.4194 mmol) and stirring was continued at ambient temperature under nitrogen for 2 hours. To this reaction was added a solution of tert-butyl (45)-4-3-(3-benzyloxy-6 sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (180 mg, 0.3470 mmol) in anhydrous tetrahydrofuran (1 mL), then 1,8-diazabicyclo/5.4.01undec-7 -ene (200 μL, 1.337 mmol) and the mixture was stirred at ambient temperature for 15 h. Volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (20 mL) and water (10 mL), and the mixture was slowly acidified with hydrochloric acid (1 .5 ml, 1.0 M, 1.500 mmol) to approximately pH - 4.0.

The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases were washed with saline (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (gradient of ethyl acetate in hexane from 0 95 to 70 9° for 35 minutes) to obtain tert-butyl (45)-4-I3-((3-benzyloxy-6-H((2-chloro-6 -I3-(3-(11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (170 mg , 2295) as a white solid. MO-IER t/2 calcd. 889.3211, found 890.5 (M--1) t; retention time: 2.32 min. (Method RH C).

Stage 2: M-(5-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2- pyridyl|sulfonyl|-2-chloro-6-I(3 -I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-

Z-carboxamide (trifluoroacetate salt) о ой Й оо / х

KU ra Z

M - MN -- 56 6 -«- KE o / Ak m a shchi

To the mixed solution tert-butyl (45)-4-3-(3-benzyloxy-b-HC2-chloro-6-I(3-I3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine -3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (80 mg, 0.08985 mmol) in anhydrous methylene chloride (2.0 mL) and trifluoroacetic acid (350 μL, 4.543 mmol) at ambient temperature under nitrogen atmosphere.Orange solution

The mixture was stirred for 1 h, and then the volatiles were removed under reduced pressure. Toluene (20 ml) was added to the residue and then concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and finally dried in oil for 2 h to obtain crude /N-(5-benzyloxy-6-I3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino) |-2-pyridyl|sulfonyl|-2-chloro-6-I3-(3-H11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (trifluoroacetate salt) (81 mg, 100 95 ). The material was transferred directly to the next stage without any purification. MO-IER p/2 calcd. 789.2687, found 790.5 (M--1)k; retention time: 1.9 min. (Method RH B ).

Stage C: (145)-20-(benzyloxy)-12,12-dimethyl-8-(3-(3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

We are from M

M MN -- -zhЖ-k dom M M this is not a sled

M-I|(B-benzyloxy-6-I3-(5,5-dimethylpyrrolidin-3-yl)upropylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I13-(3 -11-

(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (80 mg, 0.08846 mmol), potassium carbonate (75 mg, 0.5427 mmol), cesium fluoride (27 mg, 0.1777 mmol) and anhydrous dimethylsulfoxide (5 ml) in the specified order. The vessel was purged with nitrogen for 2 minutes, capped, and stirred at 160 °C for 15 hours. The reaction mixture was allowed to cool to ambient temperature, and the heterogeneous mixture was diluted with ethyl acetate (30 mL) and water (20 mL) and acidified with hydrochloric acid (1 .5 mL, 1.0 M, 1.500 mmol). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22), 5,7,9,19(23),20-hexane-2,2,4-trione (55 mg, 82 95) as a white solid. MO-IER Ip/2 calcd 753.29205, found 754, 5 (Ma) Kc, holding time: 2.11 min. (Method RK 5).

Stage 4: (145)-20-hydroxy-12,12-dimethyl-8-(3-13-1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3, 9,11,18,23-pentaaztetracycloi!17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 255 ) in, uz

FIGHT ra on

M 2 Mnke 0-Y OM x sh called m du t vd - du

To a stirred solution of (145)-20-(benzyloxy)-12,12-dimethyl-8-(3-13-|1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trione (42 mg, 0.05572 mmol) in anhydrous methanol (5 ml) was added 10 95 Ra on charcoal (wet,

Oedizza) (8 mg, 0.007517 mmol) in a nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (from a cylinder) for 2.5 hours at ambient temperature.

The hydrogen cylinder was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethylsulfoxide (1.5 mL) and filtered through a syringe disk filter

MUpaitap with PTFE 0.45 μm. The sample was purified using reverse-phase preparative

From the HPLC-MS column Hypa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art: 000-4252-00-АХ), (run with a double gradient from 30 9o to 99 95 acetonitrile in water for 15 minutes (without modifier)| with obtaining (145)-20-hydroxy-12,12-dimethyl-8-(3-73-

P-"trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!yl17.3.1.111,14.05,10|hetracose-1( 22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 255) (27 mg, 72 95) as a pale blue-green solid. 1H NMR (400 MHz,

Meipapo!-a4) b 8.25 (a, U - 2.6 Hu, 1H), 7.82 (a, 9 - 8.1 Hu, 1H), 7.19 (a, U - 7.8 Hz, 1H), 6.98 (y, 9 - 8.3 Hz , 1H), 6.89 (a, 9 - 7.8 Hz, 1H), 5.97 (9, U - 2.9 Hz, 1H), 4.241979 -6.1 Hz, 2H), 4.03 (I, U - 12.68

Hu, 1), 3.42 - 3.32 (t, 1H), 3.14 (41, U - 13.9, 4.4 Hu, 1H), 2.85 (5, 1H), 2.32 - 2.09 (t, 1H), 1.99 - 1.83 (t, 4H), 1.80 - 1.74 (t, 2H), 1.74 - 1.66 (t, 2H), 1.66 (5, ЗН), 1.63 - 1.60 (t, 1Н), 1.59 (5, ЗН), 1.40 (da, U - 13.3, 10.1 Gu, 1H), 0.98 - 0.92 (t, 2H), 0.69 (give, 9 - 6.0, 4.2, 3.0 Hz, 2H). MO-IER t/27 calc. 663.24506, found 664.4 (M'-1) k; retention time: 1.7 min. (Method РХ 0).

Example 82: Preparation of (145)-8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3. 1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 256)

G oh Zhe you He Y she ko. ru and Mi ver Ge; y I --- M ME M M y y KHAI

Stage 1: tert-butyl (45)-4-3-((6-Ce-chloro-6-I3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridin-3-carbonyl) |sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate thyro

M - - -0680950-0О- d- Mn i M SI in ha de a 2-chloro-6-IZ-K(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|Ipyridin-3- carboxylic acid (200 mg, 0.5717 mmol) and carbonyldiimidazole (116 mg, 0.7154 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether, and dried under high vacuum) were combined in tetrahydrofuran (2 mL) and stirred for 2 h at room temperature. Then tert-butyl (45)-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (275 mg, 0.6666 mmol) was added, followed by 1,68-diazabicyclo|5.4.Fundec-7-ene (500 μL, 3.343 mmol), and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried ( magnesium sulfate), filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100 95 hexanes to 10095 ethyl acetate to give tert-butyl (45)-4-I3-((6-Ce-chloro-6 -IZ3-K(2,2,3,3- tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (172 mg, 4095) in the form of an off-white solid. MO-IER t/2 calcd. 743.3232, found 744.45 (M.--1)x; retention time: 0.97 min. (Method RH A) .

Stage 2: (145)-8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111 ,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 256)

Her B

- (9) sob with

M. - M ikh xx M sh 0 M si | N al hi -- yin

Solution of tert-butyl (45)-4-3-(6-C2-chloro-6-I3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl| -2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (172 mg, 0.2311 mmol) in dichloromethane (1.5 mL) and trifluoroacetic acid (500 μL, 6.534 mmol) was stirred at room temperature for 4 hours. The solvents were removed, and the residue was dissolved in ethyl acetate. It was washed with 2 mL of saturated aqueous sodium bicarbonate solution, the organic layer was collected, and the solvent was removed in vacuo. The residue was dissolved in dimethyl sulfoxide (10 mL), 3 A molecular sieves were added, and the reaction mixture was stirred for 10 min Then it was added

Cesium fluoride (115 mg, 0.7571 mmol) and potassium carbonate (107 mg, 0.7742 mmol) were added, and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and to saturated ammonium chloride solution was added to the filtrate. The mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by reversed-phase HPLC-MS using a column

Hypa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art.: 00С-4252-00-

AH), and a double gradient from ЗО 95 to 99 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile. Flow rate - 50 ml/min, volume injection - 950 μl and the temperature of the column - 25 "C) to obtain (145)-8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab6-thia-3,9,11, 18,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 256) ( 19.5 mg, 17 905) as an off-white solid. 1H NMR (400 MHz, DMSO-ab) b 12.58 (5, 1H), 10.63 (5, 1H), 8.22 (y, 9 - 2.7 Hu, 1H), 7.87 (y, Y - 7.8 Hz, 1H), 7.65 (5, 1H), 7.13 (a, Y - 6.9 Hz, 1H), 6.94 (y, Y - 8.2 Hz, 1H), 6.79 (5, 1H), 6.00 (a, U - 2.7 Hz, 1H), 4.02 (a, U - 12.8 Hz, 1H), 3.27 (a, U - 5.2 Hz, 1H), 3.04 (j, U - 13.3 Gu, 1H) . 1.66 (y, U - 13.3 Hz, 5H), 1.61 (5, ЗН), 1.49 -

1.36 (t, 1H). MO-IER t/2 calc. 497.1845, found 498.33 (M.-1)-; retention time: 1.47 min. (Method of RH B).

Example 83: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)-2-hydroxyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6 -thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2 ,4-trione (Compound 257) (9) (9) o "J lu o o y M (Fe) M sh- y M (o) ko vier 1 i. - vier2 For --- -- -о754 weaver Z o x U / Z y- fin o x | 5 (o) (9) (e) Y -. хх ра у -- M V and 5 y

SI M SI

(in)

Gi KYA in the same Mk ME ts i -Yay zerb KI 5-4 MU a Toner? o hg 5 d- ay oo o o oy ІІ y r re zh t s s -0 te si - vivr8 s -0 Mi vogf zivr9 about them

Stage 1: tert-butyl-3-(2-dispiro|2.0.2.1|)heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (c)

M r ra o) o o y M (c) d-

OK "

A solution of n-Vyg (16 ml of 2.5 M in hexane, 40,000 mmol) was added to a solution of diisopropylamine (4.0432 g, 5.6 ml, 39.957 mmol) in tetrahydrofuran (50 ml), which had previously been cooled to -30 C (bulb 1). The mixture was stirred for 20 minutes in an ice water bath before cooling to -78 "C. In a separate flask, ethyl dispiro(|2.0.2.1|heptane-7-carboxylate (1.66 g, 9.9869 mmol) was dissolved in 100 ml of tetrahydrofuran. Chloro(iodine)methane (8.8112 g, 3.7 mL, 48.956 mmol) was added and the solution was cooled to -78 "C in a nitrogen cylinder (flask 2). The contents of flask 1 were transferred through a cannula for x 15 min (very quickly dropwise) into flask 2. The resulting mixture was further stirred at -78 "C for 1 hour. A mixture of acetic acid/tetrahydrofuran (15 ml/15 ml) was added dropwise. The dry ice bath was removed and the mixture was allowed to warm to -0 C. It was then partitioned between water and ethyl acetate.The layers were separated and the aqueous layer was washed again with ethyl acetate.The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.

The residue was dissolved in M,M-dimethylformamide (15 ml) at room temperature. They added a third

butyl 3-hydroxypyrazole-1-carboxylate (810 mg, 4.3976 mmol), followed by potassium carbonate (1.25 g, 9.0445 mmol) and potassium iodide (62 mg, 0.3735 mmol). The mixture was stirred at 60°C for 48 hours. It was then cooled to room temperature and diluted with ethyl acetate/water (30 mL each). The layers were separated and the aqueous layer was extracted again with ethyl acetate (20 mL). The combined organic layers were washed water (20 mL), brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel using a gradient of 5 95 to 40 95 ethyl acetate in hexane. The desired product (less polar isomer) tert-butyl-3- (2-Dispiro|2.0.2.1|)heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (620 mg, 47 95) as a white solid. 1H NMR (250

MHz, Spiogoiogite-4) b 7.85 (5, 1H), 5.96 (5, 1H), 4.95 (5, 2H), 2.62 (5, 1H), 1.60 (5 9H), 1.34 - 1.16 (t, 2H), 1.14 - 0.63 (t, 6Н). MO-IER t/2 calc. 318.158, found 319.5 (Ma-1)k; Holding time: 3.59 min. (The method of RH R).

Stage 2: tert-butyl-3-(2-dispiro/2.0.2.1|heptan-7-yl-2-hydroxyethoxy)pyrazole-1-carboxylate and Xa m

ЖЖ no 5-0 c) (c) ek - 565656 - "Ж о ш-Щ- 5 I

Tert-butyl-3-(2-dispiro/2.0.2.1|)heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (620 mg, 1.7527 mmol) was dissolved in ethanol (10 mL) and the mixture was cooled in a bath of ice water.

Sodium borohydride (66.309 mg, 0.0702 mL, 1.7176 mmol) was added. After 5 minutes, methanol (0.5 ml) was added. The mixture was stirred at room temperature for 1 hour. Then quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water (20 ml each). The layers were separated and the organic layer was filtered through a pad of anhydrous sodium sulfate and concentrated. The crude material was used in the next step without further purification, tert-butyl-3-(2-dispiro|2.0.2.1|heptan-7-yl-2-hydroxyethoxy)pyrazole-1-carboxylate (600 mg, 91 95). MO-IER t/2 calc. 320.1736, found 321.3 (М-а1)ж; retention time: 3.44 min. (The method of RH R).

Stage C: tert-butyl-|1-dispiro|2.0.2.1|heptan-7-yl-2-(1H-pyrazol-3-yloxy)ethoxy|dimethylsilane (c) x )

M X Z and M for | by

Tert-butyl-3-(2-dispiro|2.0.2.1|heptan-7-yl-2-hydroxyethoxy)pyrazole-1-carboxylate (300 mg, 0.8896 mmol) was dissolved in dichloromethane (10 mL) and the mixture was stirred in baths with ice water under a nitrogen cylinder. 2,6b-lutidine (686.96 mg, 0.75 mL, 6.3469 mmol) was added, and then

TVOM5OTI (1.2408 g, 1.1 ml, 46001 mmol). The mixture was stirred for 30 min. More 2,6-lutidine (551 mg, 0.6 mL, 5 mmol) was added, followed by TVOM5OTI (1.2408 g, 1.1 mL, 4.6001 mmol). The mixture was stirred for 12 hours. It was then diluted with dichloromethane (40 mL) and treated with saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 95 to 30 95 ethyl acetate in hexane to give tert-butyl-|!-dispiro(2.0.2.1|heptan-7-yl-2-(1H-pyrazol-3-yloxy) ethoxy|dimethylsilane (300 mg, 81 95) in the form of a colorless oil. MO-IER t/72 calcd. 334.2077, found 335.6 (M--1) k; retention time: 4.55 min. (RC method R).

Stage 4: tert-butyl-6-I3-(2-(tert-butyl(dimethyl)silyl|oxy-2-dispiro|2.0.2.1|)heptan-7-ylethoxy|pyrazol-1-yl|-2-chloro -pyridine-3-carboxylate

IN

Moss: Kk ho-u Zh b i sh-- i 5 o i- M. ru r o -0.Y M si si M si i sh-

Tert-butyl (1-dispiro(/2.0.2.1|heptan-7-yl-2-(1H-pyrazol-3-yloxy)ethoxy|dimethylsilane (300 mg, 0.8071 mmol)) was dissolved in dimethyl sulfoxide (8 mL) at tert-butyl 2,6-dichloropyridine-3-carboxylate (210 mg, 0.8464 mmol) was added, followed by potassium carbonate (138 mg, 0.9985 mmol) and 1,4-diazabicyclo|2.2.2|octane (18 mg, 0.1605 mmol).The mixture was stirred at room temperature for 24 h.Ethyl acetate (-25 mL) was added followed by water (--20 mL).

The layers were separated and the aqueous layer was extracted again (-20 mL) with ethyl acetate. The combined organic layers were concentrated and the residue was purified by chromatography on silica gel using a gradient of 0-1095 ethyl acetate in hexane to give // tert-butyl-6-|3-(2-It-tert-butyl(dimethyl)silyl|oxy-2- dispiro|2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylate (490 mg, 100 95) as a white solid 1H NMR (250 MHz, chloroform-α) 68 .35 (dd, U - 2.8,0.9 Hz, 1H), 8.19 (dd, U - 8.4,0.9 Hz, 1H), 7.68 (dd, U - 8.4 ,0.9 Gu, 1H), 5.93 (dd, uh 2.9,0.9 Hz, 1H), 4.17 (dd, U - 5.5, 0.9 Hz, 2H), 4, 01-3.80 (m, 1H), 1.78-1.43 (m, 1H), 1.38-1.16 (m, 4H), 1.15--0.45 (m, 22H) , 0.20--0.01 (m, 6Н).

Stage 5: 6-(3-(2-Et-butyl (dimethyl)silyl|oxy-2-dispiro|2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylic acid) (c) priest and: on

Mo U, 8i-- M. ro o - M si for Sho a de

Tert-butyl 6-3-(2-I(tert-butyl (dimethyl)silyl|oxy-2-dispiro(2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylate (200 mg, 0.3296 mmol) was dissolved in dichloromethane (4 mL) and cooled in an ice-water bath.Triethylamine (200.11 mg, 0.2756 mL, 1.9776 mmol) was added, followed by TBM5OH (609.8 mg, 2.3072 mmol.) The mixture was stirred at room temperature for 5 h and diluted with dichloromethane (10 mL).

Water (10 ml) was added and the layers were separated. The dichloromethane layer was concentrated, and the residue was purified by chromatography on silica gel using a gradient of 0 to -10 90 methanol/dichloromethane to give 6-IZ-(2-(tert-butyl (dimethyl)silyl|oxy-2-dispiro|2.0.2.1| heptane-7-ylethoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylic acid (50 mg, 22 95). 1TH NMR (250 MHz, SPiogotogit-4) b 8.49 - 8.17 (t, 2H), 7.70 (а, 9- 8.4 Hz, 1Н), 5.94 (а, у-2.9HZ, 1Н), 4.16 (0, у - 5.4 Hz, 2Н), 3.89 (ai, У - 8.6, 5.4 Hz, 1Н), 1.65 (I, U - 7.6 Hu, 1H), 1.12 - 0.41 (t, 19H), 0.06 (a, U - 2.2 Hz, 6H). MO-IER t/: calculated 489.1851, found 490.7 (M '-1) k; time

From maintenance: 4.53 min. (The method of RH R).

Stage 6: tert-butyl-(45)-4-(3-(6-((6-(3-(2-(tert-butyl(dimethyl)silyl|oxy-2-dispiro|2.0.2.1|heptane- 7-ylethoxy|pyrazol-1-yl|-2-chloropyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate o 95 I z- M-m M si x - with kl 5-4 7 Y To 6-I3-(2-Egret-butyl (dimethyl)silyl|oxy-2-dispiro(|2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|-2-chloropyridine -3-Carboxylic acid (750 mg, 1.5304 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature under a nitrogen balloon.Carbonyldiimidazole (345 mg, 2.0851 mmol) was added in one portion.The reaction mixture was stirred for 4 h. Tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (695 mg, 1.6847 mmol) was weighed into a separate flask and added and tetrahydrofuran (5 mL) followed by 1,8-diazabicyclo/5.4.0undec-7-ene (249.90 mg, 0.25 mL, 1.6087 mmol).The activated acid mixture was then transferred to a solution of 1,8- diazabicyclo/5.4.0)undec-7-ene using a pipette. The resulting mixture was mixed stored at room temperature for 14 hours. Then the mixture was concentrated, transferred to ethyl acetate (-30 ml) and washed with saline solution. The organic fraction was dried (sodium sulfate), filtered and concentrated. Purified by chromatography on silica gel using a gradient of 25-80 95 ethyl acetate in hexane, giving tert-butyl (45)-4-

I3-C6-CO-I3-(2-I(tert--butyl. (dimethyl)silyl|oxy-2-dispiro(2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|- 2-chloropyridin- 3-Carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (500 mg, 35 95) as an oil MO-IER Ip/2 calcd 883.3889, found 884.8 (M--1)-k, retention time: 5.39 min (method RH R).

Stage 7: 6-(3-(2-Itret-butyl (dimethyl)silyl|oxy-2-dispiro|2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|-2-chloro-M-(6 -(3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|isulfonyl|pyridine-3- carboxamide it she MU oyi -- -57 i- (c) same 9 and nm we and Y a a

Tert-butyl (45)-4-I3-C6-C6-(3-(2-(tert-butyl (dimethyl)silyl|oxy-2-dispiro|2.0.2.1|heptan-7-ylethoxy|pyrazole-1- yl|-2-chloropyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (500 mg, 0.5370 mmol) was dissolved in dichloromethane (15 ml) and cooled in a bath with ice-water. Triethylamine (232.32 mg, 0.3200 mL, 2.2500 mmol) was added, followed by dropwise addition of THOMA (1.1510 g, 1.0000 mL, 4.2672 mmol). The mixture was then stirred at at room temperature for 15 h, and then diluted with dichloromethane (- 20 ml) and quenched with saturated aqueous sodium bicarbonate (20 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and

They concentrated. The residue was purified by chromatography on silica gel using a gradient of 0-595 methanol in dichloromethane to give 6-I3-(2-I(Itret-butyldimethyl)silyl|oxy-2-dispiro|2.0.2.1|heptan-7-ylethoxy|pyrazole-1 -yl|-2-chloro-M-((6-(3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide) (310 mg, 70 95). MO-IER t/2 calcd. 783.3365, found 785.0 (M--1) k, retention time: 3.29 min. (Method RH R).

Stage 8: (145)-8-(3--2-T-butyldimethylsilyl)oxy)|-2-Idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-12 ,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|)hetracose-1(23),5,7,9,19,21-hexane -2,2,4-trione

(c) b oo B

M eh M kh

In "Zh kh et kh | M t she a -x uzh M ns s M 2 -- - oh I eat, oh with d- Mn

OB about 6-I3-(2-I-tert-butyl(dimethyl)silyl|oxy-2-dispiro|2.0.2.1|heptan-7-ylethoxy|pyrazol-1-yl|-2-chloro-M-(6 -(3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (310 mg, 0.3952 mmol) was dissolved in dimethyl sulfoxide (40 mL). 5 potassium carbonate (329 mg, 2.3805 mmol) followed by molecular sieves (0.3952 mmol). The mixture was degassed and protected under a nitrogen balloon. It was then heated in an oil bath at 1407 for 12 hours. After cooling to room temperature, the mixture diluted with brine (20 mL) and extracted with dichloromethane (2 x 20 mL). The solvent was removed and the residue was purified using a short pad of silica gel, eluting with ethyl acetate, to give (145)-8-(3--2-T-butyldimethylsilyl)oxy |-2-dispiro|2.0.2.1|)heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1 (23),5,7,9,19,21-hexane-2,2,4-trione (170 mg, 55 Fo) (170 mg, 55 965) . 1H NMR (250 MHz, Spiogothogt-a) b 8.20 (a, 9 - 2.8 Hz, 1H), 8.08 (y, U - 68.4 Hu, 1H), 7.67 - 7.42 (t,2H), 7.33 -7.19 (c, 1H), 6.57 (0, t 7.7 Gu, 1H), 5.90 (a, 1H), 4.69 (5, 1H), 4.17 (a, U - 5.4 Hz, 2H), 4.02 - 3.73 (t, 2H), 3.54 -2.88 (t,

ЗН), 2.61 (t, 1Н), 2.05 (t, 1Н), 1.77 -1.40 (t, 8Н), 1.26 (5, 6Н), 1.11 - 0.45 (t, 17Н), 0.08 (25, 6Н).

MO-ER t/2 calc. 747.3598, found 748.8 (M--1)k; Holding time: 4.9 min. (The method of RH R).

Stage 9: (145)-8-IZ3-(2-Idispiro(2.0.2.1|heptan-7-yl)-2-hydroxyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia -3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 257) oh oh Her and

In sote vOsho with M and M 5 - MH and dzh- MH (145)-8-(3-42-C tert-butyldimethylsilyl)oxy|-2-/dispiro(2.0.2.1|)heptan-7-idanHshshuletoxy)- 1H -pyrazol-1-yl)-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7 ,9,19,21-hexane-2,2,4-trione (170 mg, 0.2273 mmol) was dissolved in tetrahydrofuran (5 mL) in a plastic bottle and cooled in an ice water bath. 70 95 hydrogen fluoride-pyridine (0.5 ml) was added. The mixture was stirred for 10 minutes at room temperature and cooled again in an ice water bath.

Another portion of 7095th hydrogen fluoride-pyridine (0.5 ml) was added and the mixture was stirred for 10 min, removing the ice water bath. A third portion of 70 U5 wt./Wt. was added. of hydrogen fluoride with pyridine (-0.5 ml) and the mixture was stirred for 10 min.

Then it was diluted with ethyl acetate (30 ml) and saline (20 ml). The layers were separated and the organic layers were concentrated under vacuum. Towards the end of solvent removal, a white precipitate was observed. The residue was treated with a mixture of ethyl acetate and water (30 ml each) and left at room temperature for - 2 hours. The layers were separated, the organic layer was concentrated, and the residue was purified by chromatography on silica gel using a gradient of 0-590 methanol in dichloromethane to give (145)-8-I3-(2-isdispiro|2.0.2.1|heptan-7-yl)-2 - hydroxyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1( 22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 257) (63 mg, 44 95). TN NMR (250 MHz, SOSIZ) b 8.20 (40.9 - 2.68 Gu, 1), 8.03 (a,

U -8.2 Gu, 1H), 7.65 - 7.36 (t, 2H), 7.18 (a, y - 8.3 Hz, 1H), 6.55 (a, U - 68.0 Hz, 1H), 5.94 (a, U - 2.8

Hu, 1H), 4.71 (5,1H), 4.38 - 4.03 (t, ZN), 4.03 - 3.70 (t, 2H), 3.33 (I, U - 8.68 Hz, 1H), 3.25 - 2.89 (t, 2H) . 1.04 - 0.76 (t, 5H), 0.67 (y, uU - 12.68 Hz, 4H). MO-IER ip/2 calc. 633.2733, found 634.4 (M--1) k; retention time: 2.87 min. (The method of RH K).

Z8o0

Example 84: Preparation of (145)-8-(3-(2-hydroxy-3-(/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab- thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10),6,8,19(23),20-hexane-2 ,2,4-trione (Compound 259) all on o o o o - 5 o fo tmvos of sulfur. x - , re June re

Aa vedy KA, ia kacha -rb

Y KU (c) o Mem sia si k Iv zivr 7 so | from north - Like 9 GeDyKe) xx /Y

OS im n y no M M - os Mn o-yi M dl ra tri

And co

Stage 1: dimethyl (2-oxo-3-/1-(trifluoromethyl)cyclopropyl|propylidene))-Ab-sulfanone (c)

Es on , gas w / with o o

2-|1-trifluoromethyl)cyclopropylacetic acid (3.0 g, 17.85 mmol) was added to the reaction vessel and dissolved in dichloromethane (30 ml). The mixture was cooled to 0 °C and M, M-dimethylformamide was added (50 μL, 0.6457 mmol) and oxalyl chloride (1.9 mL, 21.78 mmol). The resulting reaction mixture was first stirred for 2 h at 0 °C, allowing it to warm to room temperature during this period. Volatiles were then removed using a rotary evaporator (vacuum set at 100 mbar, water bath at 20 °C) to obtain the desired pure acid chloride . Chlorine chloride solution was used directly without additional purification. In a separate vessel, trimethylsulfoxonium iodide (12.2 g, 55.44 mmol) was added and dissolved in tetrahydrofuran (30 ml). Potassium tert-butoxide (6.2 g, 55.25 mmol) was added as a 1 M solution in tetrahydrofuran, and the resulting mixture was heated under reflux for 2 hours. The mixture was cooled to 0 °C and the chloride obtained above was added as a solution in tetrahydrofuran (30 ml), maintaining the temperature below 5 °C. The mixture was stirred at 0 "C for 1 hour. Celite was added to the mixture, then filtered through Celite (washing solids with ethyl acetate and concentrating volatiles by rotary evaporation). The resulting mixture was washed with water in a separatory funnel and extracted with ethyl acetate (2 x 100 ml).

The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give dimethyl (12-oxo-3-(1-(trifluoromethyl)cyclopropyl|propylidene))-Ab-sulfanone (1.9 g, 44 95) in the form of oil. TN NMR

Zo (400 MHz, Spiogotogt-a) b 3.39 (5, 6H), 2.99 (5, 1H), 2.40 (5, 2H), 1.01 (a, U - 2.0 Hz, 2H), 0.94 - 0.81 (t, 2H ). MO-IER t/2 calc. 242.05884, found 243.2 (М--1)хж; Holding time: 0.72 min. (Way

RK E).

Stage 2: 1-chloro-3-(1-trifluoromethyl)cyclopropyl|propan-2-one (c)

Es z z es s / є (in) (in)

Dimethyl (12-oxo-3-(1- (trifluoromethyl)cyclopropyl|propylidene))-Ab-sulfanone (1.9 g, 7.843 mmol) dissolved in dry tetrahydrofuran (16, 0 ml). and then hydrochloric acid (4 M in dioxane) (2.5 mL 4 M, 10.00 mmol) was added. The resulting mixture was heated to 60 °C and stirred for 3 hours.

The solvent was evaporated under vacuum (130 mbar and a water bath at 20 C) and the resulting residue was partitioned between ethyl acetate and water, then a little saline solution was added and the layers were separated. The organic layer was washed with saline solution, dried over sodium sulfate, filtered and concentrated in a vacuum (100 mbar, water bath at 30 "C) to obtain 1-chloro-3-pP-«(trifluoromethyl)cyclopropyl|Ipropan-2-one ( 1.57 g, 100 90) in the form of orange oil. 1H

NMR (400 MHz, chloroform-4) b 3.70 (s, 2H), 2.04 (s, 2H), 1.17-1.05 (m, 2H), 0.85 (tt, y - 3 ,6, 2.8, 2.2 Hz, 2H).

Stage C: tert-butyl 3-(2-oxo-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate

M shd- -y- (c) what,

To a 100 mL flask filled with nitrogen was added tert-butyl-3-hydroxypyrazole-1-carboxylate (1.20 g, 6.515 mmol), potassium carbonate (1.81 g, 13.10 mmol), and sodium iodide (11 mg , 0.07339 mmol), dissolved in M,M-dimethylformamide (15 ml). The mixture was stirred for 5 minutes, and then 1-chloro-3-(trifluoromethyl)cyclopropyl|Ipropan-2-one (1.57 g, 7.827 mmol) was added as a solution in M,M-dimethylformamide (10 mL). . The resulting mixture was heated at 65" for 16 h. The reaction mixture was poured into a saturated saline solution. The material was extracted with ethyl acetate (2 x 150 ml), the organic layers were combined, washed with water (2 x 150 ml), dried over sodium sulfate, filtered and The orange residue was purified by chromatography on silica gel using a gradient from 100 90 hexanes to 60 95 ethyl acetate in hexane to give tert-butyl-3-(2-oxo-3-H11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1- carboxylate (700 mg, 31 95) in the form of a light yellow oil. NMR (400 MHz, Spiogotogit-a) b 7.86 (a, 9 - 2.8 Hz, 1H), 5.96 (a, Y - 2.68 Hz, 1H), 4.93 (v, 2H), 2.77 (v, 2H), 1.60 (5, 9H), 1.15 - 1.07 (t, 2H), 0.91 - 0.86 (t, 2H). MO-IER tp/2 calc. 348.1297, found 349.2 (M--1) k; Retention time: 1.73 min (Method RH E).

Stage 4: 1-(1H-pyrazol-3-yloxy)-3-/1-trifluoromethyl)cyclopropyl|Ipropan-2-one o M o M -MH 37 ZY sh- sia

Es g

To the solution / tert-butyl-3-(2-oxo-3-P1-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1-

To the carboxylate (700 mg, 2.010 mmol) in dichloromethane (14 mL) was added trifluoroacetic acid (3.1 mL, 40.24 mmol) and the mixture was stirred for 1 hour. The solvent was removed, the resulting oil was evaporated and dried in vacuo to give a light yellow solid. The solid was dissolved in ethyl acetate, a saturated aqueous solution of sodium bicarbonate was added, and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-(1H-pyrazol-3-yloxy)-3-(/1-trifluoromethyl)cyclopropyl|propan-2-one (498 mg, 100 95) . MO-IER t/72 calc. 248.07726, found 249.2 (M--1)f; Holding time: 1.11 min. (Method of RH E).

Stage 5: tert-butyl 2-chloro-6-(3-(2-oxo-3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridine-3-carboxylate) hu oh

From -- 7 | ro o m We si vs si M si ZY

Es

Tert-butyl 2,6-dichloropyridine-3-carboxylate (497 mg, 2.003 mmol), 1-(1H-pyrazol-3-yloxy)-3-P1-(trifluoromethyl)cyclopropyl|propan-2-one (498 mg 2.006 mmol) and potassium carbonate (625 mg, 4.522 mmol) were combined in anhydrous dimethyl sulfoxide (14 mL). 1,4-diazabicyclo(2.2.2|octane (45 mg, 0.4012 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (16 mL) and stirred for 15 minutes. The resulting mixture diluted with ethyl acetate and washed with water (3 x 50 ml).

The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The orange residue was purified by silica gel chromatography using a gradient of 100 95 hexanes to 60 95 ethyl acetate in hexane to give a light yellow oil which was then dried in vacuo to give tert-butyl-2-chloro-6-(3-(2- oxo-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (500 mg, 54 95). 1H

NMR (400 MHz, Spiogottt-a) b 8.38 (a, 9 - 2.8 Hz, 1H), 8.18 (a, U - 8.4 Hu, 1H), 7.59 (y, U - 8.4 Hz, 1H), 6.04 (a, 9 - 2.68 Gu, 1H), 4.87 (5, 2H), 2.79 (5, 2H), 1.62 (5, TON), 1.14 - 1.09 (t, 2H), 0.85 (aa,

In - 3.0, 1.7 Hz, 2H). MO-IER t/:2 calc. 459.11728, found 460.2 (M--1)k; Holding time: 2.21 min. (Method of RH E).

Stage 6: 2-chloro-6-I(3-(2-oxo-3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridin-

Z-carboxylic acid o (6) to o z ru o M. d o o u M si

EC

Es

Tert-butyl-2-chloro-6-N3-(2-oxo-3-P1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (500 mg, 1.087 mmol) was dissolved in dichloromethane. (11 ml) and cooled to 0 "C in an ice bath. Hydrochloric acid (1.5 ml of 4 M in dioxane, 6,000 mmol) was slowly added to the mixture and the mixture was stirred at 0 "C for 1 hour. Additional hydrochloric acid (5 .5 ml of 4 M in dioxane, 22.00 mmol) and stirred for 30 minutes at 0 "C, then 2 hours at room temperature. An additional amount of hydrochloric acid (5.435 ml of 4 M in dioxane, 21.74 mmol) was added and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to a white solid which was then suspended in diethyl ether, filtered and resuspended in diethyl ether. The solid was collected by vacuum filtration and dried under vacuum for 20 hours to give /2 -chloro-6-I3-(2-oxo-3-(11-(trifluoromethyl)cyclopropyl|propoxy|pyrazo 1-1-yl|pyridine-3-carboxylic acid (237.5 mg, 54 Fo) as a white solid. MO-IER Ip/2 calc. 403.05466, found 404.2 (Ma) Kc;

Holding time: 1.59 min. (Method of RH E).

Stage 7: tert-butyl (45)-4-I3-((b-C(e-chloro-6-(3-(2-oxo-3-|1- (trifluoromethyl)cyclopropyl|propoxy|pyrazole-1- yl|pyridine-3-carbonyl|sulfamoyl|-2-

Zo pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate 9)

HoDyKe) 5 o dnk zhu You uh and shcha | r y z |v seg y

M M si - t 57-A VosMm Mn o -47 shcha si -y vsh shchi d- VosM MN a ko; x17 2-chloro-6-I3-(2-oxo-3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (166 mg, 0.4112 mmol) and carbonyldiimidazole (75 mg, 0.4625 mmol) were combined in tetrahydrofuran (4.0 mL) and stirred for 110 min at room temperature. Tert-butyl (45)-2,2-dimethyl-4-13-(b-sulfamoyl) was then added -2- pyridyl)amino|propyl|pyrrolidine-1-carboxylate (187 mg, 0.4533 mmol) followed by the addition of anhydrous 1,8-diazabicyclo/5.4.O0)undec-7-ene (160 μl, 1.070 mmol), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and then with saline. The organic layer was dried over sodium sulfate, filtered, evaporated and then purified by chromatography on silica gel using a gradient of 100 90 hexanes to 100 95 ethyl acetate followed by a second column of silica gel using a gradient of 100 95 dichloromethane to 1595 methanol in dichloromethane to give tert-butyl (45)-4-IZ3-C6-Ce-chloro-6-I3-(2-oxo-3-/1-trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridin-3-carbonyl| Isulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-i-carboxylate (173.7 mg, 53 95) as a white solid. MO-IER Ip/2 calc. 797.25854, found 798.2 (Ma) k;

Holding time: 2.21 min. (Method of RH E).

Stage 8: tert-butyl (45)-4-I3-((6-Ce-chloro-6-I3-(2-hydroxy-3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin- 3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

ZL - VosM mn 5-7 -Y VosM mn

To the stirred solution tert-butyl (45)-4-IZ-KC6-Ce-chloro-6-I(3-(2-oxo-3-(1- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine -3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (80 mg, 0.1002 mmol) in methanol (1.25 mL) under a nitrogen atmosphere and added sodium borohydride (10 mg, 0.2643 mmol), in portions to control significant boiling. After the addition was complete (which took 1 minute), the reaction mixture was a solution. The reaction mixture was concentrated on a rotary evaporator, then diluted with ethyl acetate and washed with water (2 x 20 mL), and then brine (1x). The organic layer was then separated, dried over sodium sulfate, filtered and concentrated. The residue was dried in vacuo to give tert-butyl (45)-4-I3-C(6-C2-chloro-6- I(3-(2- hydroxy-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|-2-pyridylIamino|propyl|-2,2-dimethylpyrrolidine-1 -carboxylate (80 MG, 100 95) in the form of a white solid substance. MO-IER I n/2 calculation 799.2742, found 800.3 (MA) k;

Holding time: 2.15 min. (Method of RH E).

Stage 9: (145)-8-(3-(2-hydroxy-3-1-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6-thia-3 ,9,11,18,23-pentaaztetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4 -trion (Compound 259) oo

M sh M ah no o u M si --Sh z m | r N I r 5-7 th VosmM MN 5 5-47 m them, Sun 5-7 d- MN

And av all

In a flask containing tert-butyl (45)-4-I3-((6-Ce-chloro-6-I3-(2-hydroxy-3-11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl| pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (80 mg, 0.09996 mmol) was added dichloromethane (2.5 mL) and hydrochloric acid (500 μl 4 M in dioxane, 2,000 mmol). After stirring for 90 min, the mixture was evaporated to dryness, then diluted with ether (5 mL) and re-concentrated on a rotary evaporator. The residue was then diluted with ether (5 mL) and concentrated again on a rotary evaporator. It was dried in vacuo overnight to of the residue, which was combined with potassium carbonate (139 mg, 1.006 mmol), molecular sieves Z A and

With dimethyl sulfoxide (3.5 ml) in a vial, purged with nitrogen, closed with a lid, heated to 15570 and stirred for 4 hours. It was cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with water (2 x 20 ml) and then with saline. The organic layer was additionally washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of 100 95 hexanes to 100 96 ethyl acetate to give (145)-8-(3-(2-hydroxy-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazole -1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10), 6,8,19(23),20-hexane-2,2,4-trione (compound 259) (27.91 mg, 42 95) as an off-white solid. 1H NMR (400 MHz,

DMSO-ab) b 12.49 (5, 1H), 8.22 (y, Y - 2.68 Hz, 1H), 7.82 (y, Y - 8.3 Hz, 1H), 7.58 (aa, Y - 8.5, 7.2 Hz, 1H), 7.05 (y, U - 7.2 Hz, 1H), 6.99 (5, 1H), 6.92 (y, U - 8.2 Hz, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.13 (0, - 2.8 Hz , 1H), 5.03 (5, 1H), 4.10 (da, 9 - 4.9, 2.4 Hz, 2H), 3.97 (y, U - 4.7 Hz, 2H), 3.16 (5, 1H), 2.95 (a, 9U - 13.4 Hz, 1H), 2.73 - 2.65 (t, 1H), 2.47 - 2.29 (t, 1H), 2.13 (5, 1H), 1.98 (44, U - 13.7, 3.4 Hz, 1H), 1.86 (aa, U - 11.6, 3.6 Hz, 1H), 1.77 (5, 1H), 1.70 - 1.63 (t, 1H), 1.61 (5, ЗН), 1.57 (y, y) - 12.4

Hu, 2H), 1.52 (5, ZN), 1.37 - 1.27 (t, 1H), 1.01 - 0.90 (t, 2H), 0.90 - 0.78 (t, 2H). MO-IER t/27 calc. 663.24506, found 664.4 (M'-1)k; retention time: 1.88 min. (Method of RH E).

Example 85: Preparation of (145)-8-I(3-(2-I6dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-22-hydroxy-12,12-dimethyl- 2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2, 2,4-trione (Compound 260) on OH

Vg Vg and 7 | eri | ts Ve ziver2

Mach MAK

MO,

OVp

VG dp OVp x o ZN verz (9) 5 d ---k 5ier 4 (c) o Mach

Mo,

Mo,

AL, M ra BU

She I zer SAD and rep AH, r ov o kA / - Ts ; - -- -- I - zier7 om y Mi

Vpo OVp o o MN, (F) t that / U. Vosm zir 8 i-gU o Fa: viv as M-ny shi Y in p, si

Eh ka

OVp zov ryh ud - Or 7 m M- vir 10 M xx si MN vir 11

With 7 la! ---k v sh- ov on o o o o i (9) (o) Y" 7 Va Ch u v / xx m I y y-

M. - M sh-

Stage 1: 2-bromo-b-nitropyridin-3-ol on on

Hg

Vg dp to 0---

M MAK mo,

Nitric acid (24.989 g, 17.685 mL, 277.60 mmol) (7095) was added to a solution of 2-bromopyridin-3-ol (46 g, 264.38 mmol) in sulfuric acid (230 mL) at 0°C. The reaction mixture The mixture was stirred at 0 "C for 30 minutes, then at room temperature for 48 hours, then poured into cold water (200 ml) and extracted with ethyl acetate (2 x 100 ml).

The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0 95 to 20 95 ethyl acetate in heptane) to give 2-bromo-6-nitropyridin-3-ol (9.2 g, 16 Fo) as a yellow solid. 1H NMR (300 MHz, SOSIZ) b 8.24 (a, 9-8.5 Hz, 1H), 7.54 (a, 9-8.5 Hz, 1H), 6.37 (Bg. 5., 1H). MO-IER t/2 calc. 217.9327, found 221.0 (M--1) zhk; retention time: 1.492 min. (The method of RK M).

Stage 2: 3-benzyloxy-2-bromo-b-nitropyridine OVp

Hg

Vg and | VG d. Mach -

SWING

MO, MO,

A solution of 2-bromo-b-nitropyridine-3-ol (9 g, 41.097 mmol) in dimethylformamide (60 mL) was added dropwise to a solution of sodium hydride (2 g, 50.005 mmol) at 0°C in dimethylformamide (30 mL). After 30 minutes, benzyl bromide (7.4776 g, 5.2 mL, 43.720 043Smol) was added, the cooling bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The crude mixture was diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL ). The combined organic layers were washed with water (2 x 75 ml), brine (100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was triturated in a mixture of ethyl acetate/heptane (9/1) (50 ml), then filtered and washed with an additional amount of ethyl acetate/heptane (9/1) (50 ml) to give 3-benzyloxy-2-bromo-b-nitropyridine (8.7 g, 68 95) as a yellow solid. NMR (300 MHz, dmMsSoO-ab) b 8.42 (9.9 - 8.5 Hz, 1H), 7.90 (a, U - 8.8 Hz, 1H), 7.30-7.59 (t, 5H), 5.43 (5, 2H). MO-

IER t/2 calc. 307.9797, found 311.0 (M--1)k; retention time: 1.956 min. (Method RK 5).

Stage 3: 2-ethylhexyl 3-|((3-benzyloxy-6-nitro-2-pyridyl)sulfanyl|propanoate

AL, ts AH, S o voi o 8 century 2nd

Mo, Mo,

To a solution of 3-benzyloxy-2-bromo-b-nitropyridine (14.5 g, 46.908 mmol), xanthophos (1.7 g, 2.9380 mmol), Rag(ava)z (1.35 g, 1.4743 mmol) in toluene (300 ml) was added 2-ethylhexyl-3-sulfanylpropanoate (11.5 g, 52.666 mmol), followed by the addition of M,M-diisopropylethylamine

Zo (12.614 g, 17 ml, 97.599 mmol). The resulting solution was pumped and backfilled with nitrogen three times, and then heated under reflux at 110 "C overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (75 mL). The combined filtrates were concentrated and the resulting residue was purified by chromatography on silica gel (gradient of ethyl acetate in heptane from 0 95 to 15 95) to obtain 2-ethylhexyl-3-(3-benzyloxy-6-nitro-2-pyridyl)sulfanyl|propanoate (20 g, 95 965).IN NMR (300 MHz, SOSIZ) 5 7.94 (a, U - 68.5 Hz, 1H), 7.32-7.51 (t, 5H), 7.09-7.17 (t, 1H), 5.25 (5, 2H), 3.97-4.12 (t, 2H), 3.51 (I, U - 6.9 Hz, 2H), 2.89 (i, U - 6.8 Gu, 2H), 1.51-1.67 (t, 1H), 1.20-1.43 (t, 8H), 0.81-0.96 (t , 6H). MO-IER t/2 calculated 446.1875, found 447.2 (Ma1)k, retention time: 4.181 min (method RH T).

Step 4: 2-ethylhexyl 3-((3-benzyloxy-6-nitro-2-pyridyl)sulfonyl|propanoate

AH. G AH, and: 4 o 8 same (c) with OVp aa g

Ge) (c)

IF co / mo, unit

M-Chloroperbenzoic acid (21 g, 77 95 w/w in tetrahydrofuran, 93.703 mmol) was added slowly to a solution of 2-ethylhexyl-3-|(33-benzyloxy-6b-nitro-2-pyridyl)sulfanyl|propanoate (20 g, 44.787 mmol) in dichloromethane (400 mL) at room temperature. The mixture was stirred at this temperature overnight. The solid was filtered off, and the mixture was washed with 10 95 sodium thiosulfate solution (150 mL), 5 96 sodium bicarbonate solution (2 x 100 mL), water (100 mL), and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-ethylhexyl-3-|((3-benzyloxy-6-nitro-2-pyridyl)sulfonyl|propanoate (20.5 g, 96 95) in in the form of a solid substance of yellow color.

Gu, 1H), 7.64 (a, 9-9.1 Gu, 1H), 7.31-7.52 (t, 5H), 5.45 (5, 2H), 4.03 (da, 9U-5.7, 2.5 Hz, 2H), 3.89- 4.00 (t, 2H), 3.04 (I, 9-7.5 Hz, 2H), 1.50-1.66 (t, 1H), 1.22-1.41 (t, 8H), 0.83-0.95 (t, 6H).

Stage 5: 2-ethylhexyl 3-((6b-amino-3-benzyloxy-2-pyridyl)sulfonyl|propanoate oo

M oo

SAM OV and AH, Languages

And with, sha (in) hu and ko in ol nm

Iron (2.4 g, 42.976 mmol) and ammonium chloride (1.7 g, 31.781 mmol). The reaction mixture was stirred at 100 "C for 1.5 h.

The dark solution was allowed to cool to room temperature, filtered through celite and washed with dichloromethane (150 mL). The filtrate was concentrated under reduced pressure.

The crude product was diluted with water (100 mL) and extracted with dichloromethane (2 x 75 mL).

The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by trituration in tert-butyl methyl ether (50 ml), the suspension was filtered and washed with tert-butyl methyl ether (50 ml). The resulting off-white solid was dried in vacuo overnight to give 2-ethylhexyl-3-((b-amino-3-benzyloxy-2-pyridyl)sulfonyl|ipropanoate (4.5 g, 96 95). MS-IR n/2 calculated 448.2032, found 449.2 (M.-1) zhk, retention time: 2.35 min. (method RH

AND).

Stage 6: 2-ethylhexyl 3-((3-benzyloxy-6-fluoro-2-pyridyl)sulfonyl|Ipropanoate)

AH, I OVp AH. Cor r sha c) 5 OVp

Her and her husband)

NM

IS

A solution of /2-ethylhexyl-3-(b-amino-3-benzyloxy-2-pyridyl)sulfonyl|Ipropanoate (4.5. ("Hg, 10.032 mmol) in hydrogen fluoride with pyridine (55.0 g, 50 ml, 554.96 mmol) was cooled to -52°C. The resulting red solution was treated with sodium nitrite (1.4 g, 20.291 mmol) and allowed to warm to room temperature. Gas evolution was observed and the reaction became orange and cloudy. The reaction mixture was stirred for overnight at room temperature and slowly poured onto ice and water (50 mL). The mixture was neutralized by careful addition of aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure with obtaining crude 2-ethylhexyl-3-((3-benzyloxy-6-fluoro-2-pyridyl)sulfonyl|propanoate (4 g, 88 95). MO-IER p/2 calc. 451.1829, found 452.2 (Mat) k, holding time: 2.46 min (Method RH I).

Stage 7: 3-benzyloxy-6-fluoropyridine-2-sulfonamide

АХ x 7 и чи / (c) z ОВy 77 Ж / их o m on M x / E

IS

1,8-diazabicyclo(5,4,0 )undec-7-ene (5.5550 g, 5.5 mL, 36.489 mmol). The reaction mixture was stirred for 1 hour at room temperature and a solution of hydroxylamine-O-sulfonic acid (10.1 g, 89.307 mmol) and sodium acetate was added (6 g, 73.141 mmol) in water (32 mL).The reaction mixture was stirred for 1 h at room temperature, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL).

The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (gradient from 10 90 to 40 905 ethyl acetate in heptane) to give 3-benzyloxy-6-fluoropyridine-2-sulfonamide (4.1 g, 82 95) as an off-white solid. TN NMR (300 MHz, DMSO-a6) 6 5.38 (5, 2H), 7.25-7.48 (t, 4H), 7.49-7.57 (t,

AN), 7.96 (ad, 9U-9.0, 6.0 Hz, 1H); 19E NMR (282 MHz, DMSOSO-ab) 5-78.5-768.2 (t, 1E). MO-IER t/7 calc. 282.0474, found 283.1 (M--1) k; retention time: 2.14 min. (The method of RH N).

Stage 8: tert-butyl (45)-4-I3-K5-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethyl-pyrrolidine-1-carboxylate

VpOo OVp

MN Ge) at 2

Z ni VosmM / pe / M- N.M M

Nm and MN

Oh yeah

Tert-butyl (45)-4-(33-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (291 mg, 1.135 mmol), 3-benzyloxy-6-fluoro-pyridine was loaded into a 20 ml ampoule under a nitrogen atmosphere -2-sulfonamide (321 mg, 1.137 mmol), anhydrous dimethyl sulfoxide (3 mL) and M,M-diisopropylethylamine (0.3 mL, 1.722 mmol). The vessel was closed with a lid and stirred at 85°C for 3 hours, then at 110°C for 16 hours, then at 120°C for 29 hours. The mixture was diluted with ethyl acetate (50 ml), water (50 ml) and 10 95 citric acid ( 10 mL). The two phases were separated. The organic phase was washed with brine (30 mL), dried over sodium sulfate, and the solvents were evaporated. The product was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 95 to 60 95 over 30 minutes) in hexane , obtaining tert-butyl (45)-4-N3-K5-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (342 mg, yield 58 95, purity 92 95) in the form of a foamy solid. 1H NMR (400 MHz, DMSO-ab) b 7.54 - 7.47 (t, 2H), 7.44 (a, 9 - 9.0 Hz, 1H), 7.41 - 7.33

Zo (t, 2H), 7.33 - 7.22 (t, 1H), 6.94 (5, 2H), 6.60 (a, U - 8.9 Hu, 1H), 6.49 (I, U - 5.5 Hu, 1H), 5.11 (5 . , 1H), 1.54-1.43 (t, 2H), 1.43-1.37 (t, 15H), 1.24 (5, ЗН). MO-IER t/2 calc. 518.2563, found 519.4 (M.-1) k; retention time: 1.88 min. (Method of RH B).

Stage 9: tert-butyl (45)-4-III-C(5-benzyloxy-6-(2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazole-1 -yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylIamino|propyl|-2,2-dimethyl- pyrrolidine-1-carboxylate

OVp ov (c) U o o - M - o MN - zh 0-47 M si 5-2 kh si I oo -ashchi ody in Vosm

2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (100 mg, 0.2779 mmol) and anhydrous tetrahydrofuran (2 ml). Carbonyldiimidazole (45 mg, 0.2775 mmol) was added and the mixture was stirred under nitrogen at room temperature for 4 h. A second amount of carbonyldiimidazole (45 mg, 0.2775 mmol) was added and the mixture was stirred at room temperature for 3 hours. In a separate 20 ml flask, tert-butyl (45)-4-(3-((5-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate) solution (121 mg , 0.2333 mmol) in anhydrous tetrahydrofuran (1 mL) was prepared under a nitrogen atmosphere and was subsequently added via syringe to the activated ether solution. .18 mL, 1.204 mmol) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere. After 17 h, the solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (25 mL) and water (25 mL). Aqueous hydrochloric acid (250 μl 6 M 1500 mmol) (final pH - 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate (vi d 0905 to 100 95 for 30 minutes) in hexane, obtaining tert-butyl (45)-4-I(3-((5-benzyloxy-6-(2-chloro-6-(3-(2-dispiro|2.0 .2.1|heptan-7-ylethoxy)pyrazol-1-yl)pyridine-3-carbonyl)| sulfamoyl|-2-pyridyliamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (99 mg, yield 49 95, purity 93 95) in the form of a colorless film. MO-IER t/2 calc. 859.34937, found 860.5 (Ma1)-; retention time: 1.82 min. (Method of RH B).

Stage 10: M-(3-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I3-( 2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt).

ОВп оо что зей ХХ 2 (U uFFakya "t ee - ) a I MN o u shch si Mn o-'Na We m she, m What in more 7

TRA

To the solution tert-butyl (45)-4-I3-((5-benzyloxy-6-(2-chloro-6-I|3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol- 1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2-

To dimethylpyrrolidine-1-carboxylate (99 mg, 0.1151 mmol) in dichloromethane (0.5 mL) and toluene (0.2 mL) was added trifluoroacetic acid (100 μL, 1.298 mmol) and the mixture was stirred at ambient temperature for 23 hours. The solvent was removed in vacuo with a bath temperature set at 40 C to form a thick yellow oil. The oil was diluted with toluene (5 mL) and the solvent was removed by refluxing at 40 °C to afford M-((Z-benzyloxy-6-|3-

I(35)-5,2-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy) pyrazol-1-yl|pyridine-3-carboxamide (trifluoroacetate salt) (100 mg, 99965) as a yellow gum MO-IER t/72 calcd 759.29694, found 760.4 (Ma-1)k; retention time: 1.9 min (Method RH B).

Stage 11: (145)-22-(benzyloxy)-8-13-(2-yldispiro(2.0.2.1|heptan-7-ilyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6 -thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2, 4-trione

VpOo

Ge) Y and

ED sx o 5-2 s si MN - to o Sh ody

TRA

To the solution M-(3-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I3-(2 -dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) (100 mg, 0.1144 mmol) in MMR (2 ml) was added potassium carbonate (180 mg , 1.302 mmol). The mixture was purged with nitrogen for 5 min. The mixture was heated at 150 rpm for 20 h. The reaction mixture was cooled to room temperature and added to water (8 mL). The mixture was carefully acidified with aqueous hydrochloric acid (500 μL 6 M, 3.000 mmol) to pH 1 to give a foamy suspension. The solid was collected by paper filtration. The wet solid was dissolved in ethyl acetate and the solution was dried over sodium sulfate, then filtered. The solvents were removed and the residue was purified by flash chromatography on silica gel using a methanol gradient (from 095 to 5595 for ZO min) in dichloromethane, obtaining (145)-22-(benzyloxy)-8-I3-(2-idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1- il|- 12,12-dimethyl-2A6- thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trione (31 mg, 37 95) as an off-white solid.

MO-0ER t/» calc. 723.3203, found 724.5 (M'-1)k; retention time: 2.19 min. (Method of RH B).

Stage 12: (145)-8-I3-(2-idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-22-hydroxy-12,12-dimethyl-2A6- thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trion (Compound 260) on o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

M FU | and m in - du

(145)-22-(benzyloxy)-8-I3-(2-yldispiro(2.0.2.1|Heptan-7-ylylethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl) was loaded into a 100 ml flask -2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5,7,9,19(23),20-hexane-2 ,2,4-trione (31 mg, 0.04282 mmol) and methanol (6 mL). The solution was purged with nitrogen. 10 95 palladium on carbon (wet, Oedizza, 21 mg, 0.01973 mmol) was added and the mixture was stirred under a hydrogen atmosphere (balloon) for 3 hours. The solution was purged with nitrogen, diluted with methanol and filtered through celite.

After evaporation of the solvents, the residue was dissolved in dimethylsulfoxide (1 ml). The solution was subjected to microfiltration and purified by preparative reversed-phase HPLC (C18) using a gradient of acetonitrile in water (from ZO 95 to 99 95 for 15 minutes, 950 μl injection, without modifier). The pure fractions were collected and the solvents were removed by evaporation.

Zo The residue was treated with dichloromethane/hexane and the solvents were evaporated to give (145)-8-(3-(2-Idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-22-hydroxy -12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (compound 260) (10 mg, 36 95) as an off-white solid. TN NMR (400

MgGu, DMOO-ab) b 12.39 (rg 5, 1H), 9.07 (Bg 5, 1H, exp. ), 8.21 (a, U - 2.68 Gu, 1H), 7.80 (bga, y - 8.0

Gu, 1TN), 7.20 (Bg 5, 1H), 6.91 (Bga, y - 8.2 Hz, 1H), 6.69 (Bbga, U - 8.8 Gu, 1H), 6.28 (Bg 5, 1H, exp.), 6.08 ( a, 9 - 2.6 Hz, 1H), 4.21 (1, 9 - 6.7 Hz, 2H), 3.77 (Bg 5, 1H), 3.20 (Brg 5, 1H), 2.96 - 2.79 (t, 2H), 2.2 (horn 5, 1H), 1.91 - 1.50 (t, 13H), 1.47 (i, 9) - 6.5 Hz, 1H), 1.42 - 1.29 (t, 1H), 0.89 - 0.78 (t, 4H), 0.68 - 0.60 (t , 2H), 0.53 - 0.44 (t, 2H). MO-IER t/: calc. 633.2733, found 634.3 (M'-1) k; retention time: 2.39 min. (Method of RH B).

Example 86: Preparation of (145)-22-hydroxy-12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 261)

OVp (in) 7 -- we M

M ho - 5-0 In M si

In t- VosM vs

ОВы ов (в) ой / X тр ры 5ier2 o M s si MN zierZ

M Ufa " Mn KO 7 i M NM

Z / -- Vosm ts koi 2TRA on p o o o sov A zhu

M m yav M

STY sia in che -2 m m Mn Z / -

Z/ and g

Stage 1: tert-butyl (45)-4-I3-C(5-benzyloxy-6-((2-chloro-6-I(3-I3-(11- (trifluoromethyl)cyclopropyl|propoxy|pyrazole-1- yl|Ipyridine-3-carbonyl I sulfamoyl/|-2-pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate оВп овп о ом / X y 7 - Mych y Mn on nzh M o Dom M sy voza I Shsh with zu Vosm and - VosM koi

Es

2-chloro-6-I3-(3-(11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid) (188 mg, 0, 4824 mmol) and anhydrous tetrahydrofuran (3 mL). Carbonyldiimidazole (75 mg, 0.4625 mmol) was added and the mixture was stirred under nitrogen at room temperature for 4 h. A second amount of carbonyldiimidazole (75 mg, 0.4625 mmol) was added and the mixture stirred at room temperature for 2 hours. In a separate flask, a 20 ml solution of tert-butyl (45)-4-(3-((5-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl|-2,2- Dimethylpyrrolidine-1-carboxylate (204 mg, 0.3933 mmol) in anhydrous tetrahydrofuran (2 mL) was prepared under a nitrogen atmosphere and was subsequently added via syringe to a solution of the activated ester. 7-ene (0.31 mL, 2.073 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 5 days.The solvents were removed under reduced pressure and the resulting thick the oil was treated with ethyl acetate (50 mL) and water (50 mL). Hydrochloric acid (450 μl 6 M, 2.700 mmol) was slowly added (final pH - 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined organic extracts were washed with saline (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate (0905 to 10095 over 30 minutes) in hexane. The product was eluted together with the impurity, which was removed during the second purification by chromatography on silica gel under the same conditions as on the first column.

Fractions containing the expected material were combined and the solvents evaporated to give tert-butyl (45)-4-3-(b-benzyloxy-6-C(2-chloro-6-I3-(3-(11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-

pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (109 mg, yield 31 95, purity 86 95) in the form of an off-white film. MOS-IER t/2 calc. 889.3211, found 890.4 (Ma1)k; Holding time: 2.49 min. (Method of RH B).

Stage 2: M-(3-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2- pyridyl|sulfonyl|-2-chloro-6-I(3 -I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-

Z-carboxamide (ditrifluoroacetate salt)

OV

ОВ о о / Х (c) ra vo Ufa m- s m ee o Dn ch si MN

We | si and MN Z / m

In M nm

Z / - Vosm, Fri 2TRA Sun

To the solution tert-butyl (45)-4-III-C(5-benzyloxy-6-|(2-chloro-6-I(3-I3-11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl| pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (109 mg, 0.1224 mmol) in dichloromethane (0.5 mL) and toluene (0.2 mL) trifluoroacetic acid (100 μl 1.298 mmol) was added and the mixture was stirred at ambient temperature for 23 hours.

Solvents were removed by mass at a bath temperature of 40 "C. The residue was diluted with toluene (5 ml) and the solvent was removed by mass at a bath temperature of 40 "C. The residue was treated with dichloromethane/hexane and the solvents evaporated to give M-I((3-benzyloxy-6-|3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2 -chloro-6-I3-(3-H11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (ditrifluoroacetate salt) (130 mg, quantitative yield) as an off-white solid. MO -IER t/2 calcd 789.2687, found 790.5 (M--1) k, retention time: 1.85 min (Method RH B).

Stage C: (145)-22-(benzyloxy)-12,12-dimethyl-8-(3-(3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

ОВ о о о по

Go! o / X -sh- r Y x m I N M xu M m MI. - xx si Mn -- U M Z / podo;

With / Fri nm ES still 2TEA odi

To a solution of M-(3-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I(3- I3-11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridin-

To Z-carboxamide (ditrifluoroacetate salt) (130 mg, 0.1277 mmol) in MMP (3 mL) was added potassium carbonate (230 mg, 1.664 mmol). The mixture was purged with nitrogen for 5 min. The mixture was heated at 150 °C for 22 h. The reaction mixture was cooled to room temperature and added to water (10 ml). The mixture was carefully acidified with aqueous hydrochloric acid.

Zo (500 μl 6 M, 3,000 mmol) to pH - 1, obtaining a foamy suspension. The solid was collected by filtration on paper. The wet solid was dissolved in ethyl acetate, the solution was dried over sodium sulfate and filtered. The solvents were evaporated and the residue was purified by flash chromatography on silica gel using a gradient of methanol (from 0 95 to 595 in 30 min) in dichloromethane to give (145)-22-(benzyloxy)-12,12-dimethyl-8-(3-13 -|1- (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)htetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (38 mg, 39 95) as a white solid. MO-IER t/2 calc. 753.29205, found 754.5 (MAT); retention time: 2.38 min. (Method of RH B).

Stage 4: (145)-22-hydroxy-12,12-dimethyl-8-(3 13-/1-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9 ,11,18,23-pentaazatetracycloi!17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 261)

he p o o o

Zh m Y en

M and I that M t -- Bi M MN

With / - Es g

(145)-22-(benzyloxy)-12,12-dimethyl-8-(3-(3-(11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl) was loaded into a 100 ml flask -2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2 ,2,4-trione (39 mg, 0.05174 mmol) and methanol (8 mL). The solution was purged with nitrogen. 10 95 palladium on charcoal (wet, Oedizza, 27 mg, 0.02537 mmol) was added and the mixture was stirred under atmosphere hydrogen (balloon) for 4 h. The solution was purged with nitrogen, diluted with methanol and filtered through celite. After evaporation of the solvents, the residue was dissolved in dimethyl sulfoxide (1 mL).

The solution was subjected to microfiltration and purified by preparative reversed-phase HPLC (C18) using a gradient of acetonitrile in water (from 30 906 to 99 95 over 15 minutes, 950 μl injection without modifier). The pure fractions were collected and the solvents were removed by evaporation.

The residue was treated with dichloromethane/hexane and the solvents evaporated to give (145)-22-hydroxy-12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl) -2A6- thia-3,9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2, 2,4-trione (compound 261) (22 mg, 63 95) as an off-white solid. IN NMR (400

MHz, DMSOO-ab) 5 12.38 (rgoaad 5, 1H), 9.07 (rg 5, 1H), 8.21 (a, 9U - 2.7 Hz, 1H), 7.79 (Bg 5, 1H), 7.20 (Bg 5, 1H) , 6.90 (Bg 5, 1H), 6.68 (Brg 5, 1H), 6.28 (Bg 5, 1H), 6.10 (Bg 5, 1H), 4.20 (I, U - 6.2 Hz, 2H), 3.76 (horn 5, 1H), 3.21 (ri 5, 1H), 2.98 - 2.75 (t, 2H), 2.12 (horn 5, 1H), 1.93 - 1.77 (t, ZN), 1.78 - 1.66 (t, ZN), 1.68 - 1.46 ( t, 8H), 1.37 (horn t, 2H), 0.95 - 0.88 (t, 2H), 0.79 - 0.68 (t, 2H). MO-IER t/2 calc. 663.24506, found 664.3 (M.-1)khk; retention time: 2.24 min. (Method of RH B).

Example 87: Preparation of 2-imino-12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9 ,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1) (compound 262) and 2-imino-12,12-dimethyl-8-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11 ,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 2) (Compound 263) si on J

SI SI o o m 0-5 Mn o MN in E 7 Their era and o Ex - zivr2

And AI | all -- zhya

M hu

E. M. E

IS

Z mn, he (c) and (c) zir Z rya s is -vyvri, in o em s v

Not me Mr

VKOAH DM

M zier 5 zier 6 av E ry X, zo Z M E

МН, 4 attention to table 5-4 Зм Е зерв х | Kk sh- naz M eE ut vs

HER Y M E called M -2U s is -d tera -7 y E - u o or v o o o

Her girlfriend? M E vok M. "iero NS M. re s | N y t

Axes - ( « RT-tNA--5 nm KU o E rad rad -K h o o o vin ge r pre n v vivr 12 M in Z-

We -- -- x43ya- 0th TM M vir 13 o-4 mm M M -- 6 5-36

She M. z - We 4 We 4 se: ry ryty

Stage 1: tert-butyl 2,6-difluoropyridine-3-carboxylate si on -«« ve o i (c) (c) MH ME / X -,khyn4RA--zhk

And n- sun

E M--

IS

To a solution of 2,6-difluoropyridine-3-carboxylic acid (10 g, 62.858 mmol) and BEZ-E2O (0.4 mL, 3.2 mmol, 0.05 equiv.) in dry tetrahydrofuran (60 mL) at 0 " C was slowly added tert-butyl-2,2,2-trichloroethaneimidate (10 g, 45.8 mmol) over 10 min. The reaction solution was stirred at room temperature for 2 h under a nitrogen atmosphere. 2-trichloroethaneimidate (20 g, 91.5 mmol) and BE3-E2O (0.4 mL) at room temperature. The reaction mixture was stirred for 1 h. It was then allowed to stand over the weekend and then quenched with saturated aqueous sodium bicarbonate solution. extracted with ethyl acetate (2 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 095 to 2095 ethyl acetate in heptane to give tert -butyl 2,6-difluoropyridine-3-carboxylate (12 g, 89 95) as a white solid. MO-IER t/2 calc. 215.0758, found 216.1 (M.-1)w; retention time: 2.13 min. (Method RH I).

Stage 2: tert-butyl o 2-fluoro-6-I3-(2-P-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxylate p Uk s (c) x -- "-kzhk (c) la! M E d-- xx

KT EME Kk pa shko, 1,4-diazabicyclo 12.2.2| octane (125 mg, 1.1144 mmol) was added to a solution of tert-butyl 2,6-difluoropyridine-3-carboxylate (1.2 G, 5.5763 mmol) and 3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy |-1H-pyrazole (1.29 g, 5.8585 mmol). The mixture was stirred for 10 minutes and potassium carbonate (1.2 g, 8.6827 mmol) was added. The mixture was stirred at 20 C under nitrogen for 16 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3 x 30 ml), brine (30 ml), dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in heptane (0-15595) , obtaining tert-butyl-2-fluoro-6-I(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylate) (1.46 g, yield 63 95 ) in the form of a white solid. IN NMR (300 MHz, SOSIS) b 0.71-0.78 (t, 2H), 1.01-1.05 (t, 2H), 1.60 (5, 9H), 2.10 (1, 9-71 Gu, 2H), 4.41 (1, 9-7.1 Hz, 2H), 5.95 (y, 9U-2.9Hz, 1H), 7.63 (da, 9U-8.2, 1.2Gu, 1H), 8.29 (y, 9-2.8 Hz, 1H), 8.32-8.38 (t, 1H). 19 E NMR (282 MHz, SOSIZ) b -69.9 (s, ZE), - 62.4 (d, U - 9.2 Hz, 1e). MO-IER t/2 calc. 415.1519, found 416.2 (M--1)k; retention time: 2.69 min. (The method of RH U).

Stage C: 2-fluoro-6-I3-(2-P1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid

J on (9) and (c) I | about Mich

M k - -- o-y.7M M E -D t y Es

Kk ko

Trifluoroacetic acid (3 ml) was added to a solution of tert-butyl-2-fluoro-6-I3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylate (1.46 g, 3.5148 mmol) in dichloromethane (12 ml). The mixture was stirred at 40 "C for 4 hours. Then the mixture was concentrated under reduced pressure and dried under vacuum to obtain 2-fluoro-6-I3-(2-1-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (1.26 g, 100 95) as a white solid. IN NMR (300 MHz, SOSIS) b 0.84-.091 (t, 2H), 0.93-0.99 (t, 2H), 2.09 (Her, U - 7.0 Gu, 2H), 4.35 (I, 9U-7.0 Hz, 2H), 6.21 (y, 9-2.7 Hz, 1H), 7.67 (a, 9U -9.3 Hz, 1H), 8.42 (y,

U-3.1Hz, 1H), 8.50 (aa, 9U-9.3, 8.5 Hz, 1H), 13.48 (Bg. 5., 1H). 19E NMR (282 MHz, SOSIZ) b -68.38 (s,

ZE), -63.25 (d, 9-95 Hz, 1). MO-IER t/72 calc. 359.0893, found 360.1 (M-1)w; retention time: 2.19 min. (Method РХ 1).

Stage 4: 2-fluoro-6-I3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-

Co) carboxamide

MN, he 2nd o and | o M. pr - - Airborne Forces in ME p- nk o

Kk KO

To a suspension of 2-fluoro-6-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (1.26 g, 3.5071 mmol) in dichloromethane ( 20 ml) was added one drop of M, M-dimethylformamide (0.015 ml) followed by the dropwise addition of oxalyl chloride (625.65 mg,

0.43 ml, 4.9293 mmol). The reaction mixture was stirred at room temperature for 2 h until the formation of bubbles stopped. The solvent was removed under reduced pressure. The resulting white solid was dissolved in anhydrous tetrahydrofuran (10 mL) and added to a mixture of 28 95 aqueous ammonium hydroxide (10 mL) and tetrahydrofuran (5 mL), which was cooled in an ice water bath. Then the reaction mixture was stirred at room temperature for 1 h, and then diluted with ethyl acetate (100 ml), washed with water (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-fluoro-6-I (3 -(2-P1-"trifluoromethyl)cyclopropyl|ethoxy |pyrazol-1-yl|pyridine-3-carboxamide (1.3 g, quantitative yield) as a white solid. 1H NMR (300 MHz, SOSIS) b 0.70- 0.79 (t, 2H), 0.99-1.08 (t, 2H), 2.10 (1, 9U-7.2 Hz, 2H), 4.42 (I, 9-7.1 Hz, 2H), 5.60 (Bg.5, 1H), 5.97 (a, U-2.9 Hz, 1H), 6.61-6.71 (t, 1H), 7.74 (da, U-8.3, 2.0 Gu, 1H), 8.28 (a, 9U-2.8 Hz, 1H), 8.62 (ad, 9U-9.6, 8.3 Hz, 1H). 19E NMR (282 MHz, SOSI 3) b -69.86 (s, ZE), -65.44 (t, U - 8.68 Hz, 1). MO-

IER t/2 calc. 358.1053, found 359.1 (M--1) k; retention time: 2.08 min. (Method RH I).

Stage 5: 2-tert-butylsulfanyl-b6-fluoropyridine i. Ж - ХК

E M E eh

With M. E

2-Methylpropane-2-thiol (9.0400 g, 11.3 mL, 100.24 mmol) was added to a suspension of sodium hydride (4.8 g, 120 mmol, 6095 in oil washed with 20 mL of anhydrous ether) in anhydrous tetrahydrofuran (200 mL) at 0 "C. The gray suspension was stirred at room temperature for 30 minutes, then 2,6b-difluoropyridine (10 mL, 110.3 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then cooled in a bath with ice water and then quenched with water. The resulting mixture was diluted with ethyl acetate (60 ml), washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-tert-butylsulfanil -6-Fluoro-pyridine (22 g, yield 96 95, purity 81 95) as a pale yellow oil, which was used directly in the next step.IN NMR (300 MHz, SOSIS) b 1.55 (5.9 H), 6.64 (ada, 9U-8.1, 2.9, 0.5 Hz, 1 N), 7.12 (aa, U - 7.6, 2.2, 0.5 Hz, 1 N), 7.57 (d, U - 8.0 Hz, 1 N). MO-

IER t/2 calc. 185.0674, found 186.1 (M--1)x; Holding time: 2.21 min. (Method RH I).

Stage 6: 6-fluoropyridine-2-thiol

At room temperature (about 20 "C), 100 ml (100 mmol) of a 1 M solution of boron tribromide in dichloromethane was added dropwise to a solution of 2-tert-butylsulfanyl-b6-fluoropyridine (22 g, purity 8195, 96.188 mmol) in 150 ml dichloromethane. The reaction mixture was stirred at room temperature for 2.5 h. Boron tribromide (50.00 ml of 1 M in dichloromethane, 50 mmol) was also added. After 10 min, the reaction mixture was diluted with 100 ml of dichloromethane, washed with water (2 x 100 ml) , vigorously shaken until two clear phases were obtained, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude b-fluoropyridine-2-thiol (28 g, yield 100 Fo, purity 45 95) in the form of a yellow oil. 13 NMR ( 300

MHz, SOSIZ) b 6.65 (yes, 9U-8.1, 2.5Hz, 1H), 7.07 (yes, 9U-7.6, 2.2Hz, 1H), 7.60 (d, 9U-7.9 Hz, 1H). 19 E

NMR (282 MHz, SOSIZ) b -66.78 (s, 1PE).

Stage 7: 2-fluoro-6-((b-fluoro-2-pyridyl)disulfanyl|pyridine

XX paradise E M 2)

YES then 5 not M E r

Bromine (17.063 g, 5.5 mL, 106.77 mmol) was slowly added to a solution of b-fluoropyridine-2-thiol (28 g, purity 45 95, 97.557 mmol) in ethyl ether (160 mL) at room temperature to give pure orange color. The addition was stopped, and the reaction mixture was diluted with ethyl acetate (100 mL), washed with a 1:1 mixture of saturated sodium bicarbonate and 10 95 sodium thiosulfate solution, brine, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in heptanes (0-20 95), to give 2-fluoro-6-(6b-fluoro-2-pyridyl)disulfanyl|pyridine (10.5 g, 8490) as a brown solid substances TN NMR (300 MHz, SOSIZ) b 6.75 (aa, U-8.0, 2.6 Hz, 1H), 7.49 (aa, 9-77, 2.1 Hz, 1TN), 7.72 (d, 9-7.7 Hz, 1H). 192 NMR (282 MHz, SOSIZ) b -66.37 (d, U - 6.8 Hz, 15).

MO-ER t/2 calc. 255,994, found 257,1 (M--1) zhk; retention time: 2.12 min. (Method RH I).

Step 8: 2-fluoro-N-(6-fluoro-2-pyridyl)sulfanyl)-6-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide)

Mn, o and M HU in Mom o z o dm M E rya

E M ek Sh same " and KU o nou ko

Bromine (310.25 mg, 0.1000 mL, 1.9414 mmol) was slowly added to a solution of 2-fluoro-6-|((6-fluoro-2-pyridyl)disulfanyl|pyridine (520 mg, 2.0289 mmol) in anhydrous acetonitrile (4 ml) at 0 C. After stirring for 2 minutes at the same temperature, the red solution was added to a solution of 2-fluoro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1- yl|pyridine-

Z-carboxamide (720 mg, 2.0095 mmol) in anhydrous acetonitrile (4 mL) and pyridine (b mL) at 0 °C. The resulting dark mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was evaporated together with toluene and purified by silica gel chromatography using a gradient of 095 to 30905 ethyl acetate in heptane to give 2-fluoro-M-(6-fluoro-2-pyridyl)sulfanyl)-6-(3-(2-(11- (trifluoromethyl )cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (700 mg, 72 95) as a white solid. MO-IER t/:2 calcd. 485.0945, found 486.1 (M.- 1) g, retention time: 2.36 min (Method RH I).

Step 9: 2-Fluoro-N-(6-fluoro-2-pyridyl)sulfinyl|-6-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide) (9) (9).

Ko da Ko -

Meta-chloroperoxybenzoic acid (355 mg, purity 7795, 1.58 mmol) was added to a solution of 2-fluoro-M-(6-fluoro-2-pyridyl)sulfanyl)-6-(3-(2-P1-(trifluoromethyl) )cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (700 mg, 1.4420 mmol) in dichloromethane (20 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 1 hour. diluted with dichloromethane (70 mL), washed with 10 95 wt/vol aqueous sodium thiosulfate, 5 95 wt/vol aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel,

By eluting with a gradient from 0 9o to 40 9o of ethyl acetate in heptane, obtaining racemic 2-fluoroM-(6-fluoro-2-pyridyl)/sulfinyl|-6-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy| pyrazol-1-yl|pyridine-3-carboxamide (700 mg, 97 95) as a white solid, MO-IER t/2 calcd 501.0894, found 502.1 (M--1) k; retention time : 2.25 min (Method RH I).

Stage 10: 4-(3-azidopropyl)-2,2-dimethyl-pyrrolidine (hydrochloride salt)

M

M and NM

Hydrochloric acid (2 mL of 4 M in 1,4-dioxane, 8.0 mmol) was added to a solution of tert-butyl 4-(3-azidopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.2 g, 4, 2496 mmol) in dichloromethane (10 mL) cooled in an ice water bath. The mixture was allowed to stir at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was co-evaporated twice with toluene (40 mL) to give crude 4-(3-azidopropyl)-2,2-dimethylpyrrolidine (hydrochloride salt) (930 mg, 100 95) as a light yellow oil. 13 NMR (300 MHz, SOSIZ) b 1.29 (5, ZN), 1.38-1.54 (t, 8H), 1.99 (aa, 9U-12.7, 7.7Gu, 1H), 2.31-2.42 (t, 1H), 2.76- 2.89 (t, 1H),

3.32-3.36 (t, ZN), 9.00 (rg.5., 1H), 9.11 (Bg.5., 1H). MO-IER t/: calc. 182.1531, found 183.2 (MA1) k; Holding time: 0.94 min. (Method RH I).

Stage 11: 2-I4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-(6-fluoro-2-pyridyl)sulfinyl|-6-I3-(2-P1-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide

HER (9) (9)

Sodium hydride (193 mg, 60 95 wt./wt. dispersion in mineral oil, 2.6 mmol) was added to a solution of 4-(3-azidopropyl)-2,2-dimethylpyrrolidine (hydrochloride salt) (528 mg, 2.4 mmol) in anhydrous M,M-dimethylformamide (10 ml) was cooled in an ice water bath. The mixture was stirred for 5 min. carboxamide (930 mg, 1.85 mmol) was added. The mixture was stirred at room temperature for 30 min and then placed in an oil bath (50 °C) and stirred for 4 h. The mixture was then allowed to cool and stand overnight. diluted with ethyl acetate (100 ml). The resulting mixture was washed with water (3 x 30 ml), brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient from 0 95 to 70 95 of ethyl acetate in heptanes to obtain 2-I(I4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-(6-fluoro-2-pyridyl) sulfinyl|-6-(3-( 2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (600 mg, 49 95) as a white solid, MO-IER t/:2 calcd 663.2363, found 664 ,3 (M'-1)g, retention time: 2.6 1 min. (Method RH I).

Stage 12: 2-I4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-((6-fluoro-2-pyridyl)sulfonimidoyl|-6-(3-(2-/1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide o z o o IN

And we are here

Ammonia (10 ml of a 0.5 M solution in 1,4-dioxane, 5 mmol) was added to a solution of 2-I4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-|((6- fluoro-2-pyridyl)sulfinyl|-6-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (580 mg, 0.87 mmol) in anhydrous acetonitrile ( 5 ml) at 0 "C.M-chlorosuccinimide (140 mg, 1.05 mmol) was added in one portion (the mixture turned orange) and the reaction mixture was stirred at 0 "C for

From 1 hour. Additional M-chlorosuccinimide (100 mg, 0.75 mmol) was added and the reaction mixture was stirred at the same temperature for 30 minutes. Then the reaction was quenched with 10 95 aqueous solution of sodium thiosulfate (w/v) and extracted with ethyl acetate (50 ml). The organic layer was washed with saline (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient from 0905 to 55590 of ethyl acetate in heptane to obtain 2-I(4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-|((6-fluoro-2 -pyridyl) sulfonimidoyl|-6-I(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide) (400 mg, 67 95) in the form of a yellow sticky solid.

Stage 13: 2-I4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-|(6b-fluoro-2-pyridyl)sulfonimidoyl|-6-(3-(2-/1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide o o mn (9) M" X m e - Сай З Кой с 5-2 А ой -680-605--О 5- 2 yo - 4

Co and Z KO Zh

A mixture of 2-I(4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-(6b-fluoro-2-pyridyl)sulfonimidoyl|- 6-I3-(2-P1-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (360 mg, 0.5304 mmol), a solution of ammonia in methanol (7 N, 1 ml) and 10 95 palladium on carbon (wet, Oedizza, 200 mg , 0.094 mmol) in methanol (10 mL) was hydrogenated under 1 atm H2 (balloon) at room temperature for 3 h. The flask was evacuated and backfilled with nitrogen. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give crude 2-| 4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-(6-fluoro-2-pyridyl)sulfonimidoyl1-6-(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy| Pyrazol-1-yl|Ipyridine-Z-carboxamide (380 mg, yield 8195 , purity 74 95) as a yellow solid. The crude product was directly used in the next step without purification. MOS-IER t/72 calc. 652.2567 , found 653.3 (MT) zhk, retention time: 1.70 min (Method RH 1).

Stage 14: 2-imino-12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9, 11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1) (Compound 262) ii 2-imino-12,12-dimethyl-8-(3-12-|(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18 ,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)tetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 2) (Compound 263)

ІІ B Dom" І B - shcha Zhe - mch Zhe 4 M y: pa prita ry o

A mixture of 2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl|-M-(6b-fluoro-2-pyridyl)sulfonimidoyl|- 6-I3-(2-P1-(trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (380 mg, 0.5822 mmol), triethylamine (239.58 mg, 0.33 mL, 2.3676 mmol) and dry dimethyl sulfoxide (25 mL) were mixed in a sealed tube at 100 "C for 4 h. The mixture was allowed to cool to room temperature, then diluted with water (100 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layers were washed with water (2 x 30 ml), brine solution (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

The residue was purified by silica gel chromatography using a gradient of 0 90 to 60 95 ethyl acetate in heptanes to give 2-imino-12,12-dimethyl-8-(3-12-(11-«) as the first elution diastereomeric pair of enantiomers trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5 ,7,9,19,21-

Z hexane-2,4-dione (pair of diastereomers 1) (compound 262) (88.76 mg, yield 23 95) as a white solid, 1H NMR (300 MHz, SOSIS) mp 0.72-0.80 (t, 2H) , 0.96-1.05 (t, 2H), 1.13-1.23 (t, 1H), 1.29-1.44 (t, 1H), 1.59 (5, ZN), 1.67-1.71 (t, 1H), 1.75 (5, ZN) , 1.82-1.94 (t, 2H), 2.00-2.31 (t, 4H), 3.09-3.34 (t, 2H), 3.60 (I, 9-11.0 Hu, 1H), 3.75-3.94 (t, 1H), 4.39 (I, 9U-7.0 Hz, 2H), 4.70- 4.80 (t, 1H), 5.86 (a, 9U-2.6 Hz, 1H), 6.47 (a, 9-8.5 Gu, 1H), 6.97 (y, 9- 8.5 Hz, 1H), 7.02 (bBg. 5., 2H), 7.30 (a, 9-7.0 Hz, 1), 7.47 (da, 9-8.2, 7.3 Hz, 1H), 8.17 (a, 9U-8.2 Hz , 1H), 8.24 (a, 9-2.6 Hz, 1H). 19E NMR (282 MHz, SOSIZ) ppm -70.0 (us. s., ZE). MO-IER t/: calc. 632.2505, found 633.3 (M--1)-4; Retention time: 3.98 min. pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaaztetracycloi!17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane- 2,4-dione (pair of diastereomers 2) (compound 263) (97.02 mg, yield 25 90) as a white solid. 1 H NMR (300 MHz, SOSI Z ) 6 0.70-0.78 (t, 2H), 0.97-1.05 (t, 2H), 1.34-1.46 (t, 2H), 1.58-1.63 (t, 7H), 1.64-1.74 (t, 2H), 1.82 (ad, 9U-11.3, 5.4 Hz, 1H), 2.08-2.12 (t, ЗН), 2.96-3.11 (t, 2H), 3.29-3.42 (t, 1H), 4.16-4.25 (t, 1H), 4.32-4.41 (t, ZN), 5.09 (bBg. 5., 2H), 5.84 (a, U-2.6 Hz, 1H), 6.53 (a, 9U-8.5 Hz, 1H), 6.96 (a, 9-8.2 Hz, 1H), 7.35 (a, 9U-7.0 Hu, 1H), 7.53 (aa, 98.5, 7.3 Hz, 1H), 8.07 (y, 9U-8.2 Hu, 1H), 8.20 (a , 9-2.6 Gu, 1H). 196 NMR (282 MHz, SOSIZ) 6 -70.0 (5, ZE). MO-IER t/ calc. 632.2505, found 633.3 (M.-1) zhk; Retention time: 3.77 min (method RH

N).

Example 88: Preparation of (145)-8-I(3-(2-I6dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-21-hydroxy-12,12-dimethyl- 2Ab-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 264) he Vg sho o -0 I ver 1 9 and ory ver?

HM |; -0608.60-07- | in vno Ri

M Mach

IS

IS

(6) (6)

HA Sho Ho otu 5. o serz tu I vyvr4 lez E -er

E E o om - Y

NA X Y x -O y- tod k 5-2 M si 5ierb c) pom I- i Y ri Sh VZ

With fur and | 7th X /

M | 2-2nd " MN zer7 ek M si MN vyy fon m si - - o-sh3fy7 - Vos-M and NK

TEA on oo / J | m

XX t-oi her Kh

M | - ; " MN 8ier9 -4 We M MN for I to - I -

Stage 1: 4-benzyloxy-2-chloro-6-fluoropyridine Hg (c)

SI in SI What x / M, Ia;

M M

E E

To a solution of 2-chloro-6-fluoropyridin-4-ol (4.62 g, 31.315 mmol) in acetonitrile (90 mL) was added cesium carbonate (15.3 g, 46.959 mmol) and benzyl bromide (5.8958 g, 4, 1 ml, 34.472 mmol).

The reaction mixture was stirred at room temperature overnight. The solution was dissolved in ethyl acetate (350 ml) and water (100 ml). The aqueous phase was removed, and the organic phase was washed with water (100 mL) and saline (75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel, eluting with a gradient of 0 95 to 10 95 ethyl acetate in heptanes, to give 4-benzyloxy-2-chloro-6-fluoropyridine (7.01 g, 94 95) as a white solid. MO-IER n/72 calc. 237.0357, found 238.1 (MAT) k; retention time: 2.38 min. (The method of RK M).

Stage 2: 2-ethylhexyl 3-((4-benzyloxy-6-fluoro-2-pyridyl)sulfanyl|propanoate o ost u d Z spetut» r. Z t FI

And E

A solution of 4-benzyloxy-2-chloro-6-fluoropyridine (6.77 g, 28.486 mmol) and diisopropylethylamine (7.4200 g, 10 mL, 57.411 mmol) in toluene (250 mL) was degassed by bubbling nitrogen for 5 minutes. Tris(dibenzylideneacetone)dipalladium (0) (783 mg, 0.8551 mmol), xanthophos (990 mg, 1.7110 mmol) and 2-ethylhexyl-3-sulfanylpropanoate (6.5280 g, 6.8 mL, 29.896 mmol) were added. ) and the mixture was heated at 125 °C overnight. The reaction mixture was concentrated under reduced pressure.

The residue was purified by chromatography on silica gel, using a gradient from О 90 to 10 95 ethyl acetate in heptane, to obtain 2-ethylhexyl-3-(4-benzyloxy-b-fluoro-2-

pyridyl)sulfanyl|propanoate (12.06 g, quantitative yield) as an orange oil. TN NMR (300 MHz, SOSIZ) b 0.80-0.95 (t, 6H), 1.19-1.43 (t, 8H), 1.51-1.63 (t, 1H), 2.77 (i, 9U-7.0 Hz, 2H), 3.37 ( I, 9U-6.9 Hz, 2H), 4.02 (ad, 9U-5.9, 1.2 Hz, 2H), 5.07 (5, 2H), 6.18 (a, 9U-1.68 Hz, 1H), 6.65 (a, 9U-1.2

Gu, 1H), 7.28-7.49 (t, 5H). 19E NMR (282 MHz, SOSIZ) b -65.7 (s, 1E). MSO-IER n/2 calculation. 419,193, found 420,2 (M--1) zhk; retention time: 2.8 min. (Method RH I).

Step 3: 2-Ethylhexyl 3-((4-benzyloxy-6-fluoro-2-pyridyl)sulfonyl|Ipropanoate (o) (o)

HA Sho Z I tu 8 r. o shk tu 7 d

E E

M-chloroperbenzoic acid (12.9 g, 57.561 mmol) was slowly added at 0 °C to a solution of 2-ethylhexyl-3-((4-benzyloxy-6-fluoro-2-pyridyl)sulfanyl|ipropanoate (12.06 g, 28.745 mmol) in dichloromethane (150 mL). The mixture was stirred at this temperature overnight. Ethyl acetate (150 mL) was added and washed with saturated sodium bicarbonate solution (100 mL) and 0.5 M sodium hydroxide solution (2 x 100 mL). The organic the phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-ethylhexyl-3-|(4-benzyloxy-6-fluoro-2-pyridyl)sulfonyl|propanoate (12.05 g, 93 95) as a colorless oil

MO-0ER t/» calc. 451.1829, found 452.2 (M'-1)k; retention time: 2.54 min. (Method RH I).

Stage 4: 4-benzyloxy-6-fluoropyridine-2-sulfonamide (c) o IV) a 4 Z Ba ШЧІ: ФИ тот

Ma M

IS

IS

To a solution of 2-ethylhexyl-3-|((4-benzyloxy-6-fluoro-2-pyridyl)sulfonyl|Ipropanoate (10.69 g, 23.674 mmol) in dimethyl sulfoxide (60 ml) was added 1,8-diazabicyclo|5.4. FO3undec-7-ene (7.0700 g, 7 mL, 46.441 mmol) The reaction mixture was stirred for 1 h at room temperature and a solution of hydroxylamine-O-sulfonic acid (13.3 g, 117.60 mmol) and sodium acetate was added (7.7 g, 93.864 mmol) in water (40 mL) at 10 "C. The reaction mixture was stirred for 1 h at room temperature, diluted with water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic the layers were washed with saline (300 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

The crude material was triturated overnight with a mixture of heptane:ethyl acetate 9:1 (100 mL).

The product was isolated by filtration. The product was redissolved in ethyl acetate and filtered through a pad of silica gel, eluting with ethyl acetate (500 mL), and concentrated to give 4-benzyloxy-6-fluoropyridine-2-sulfonamide (5.56 g, 83 95). IN NMR (300 MHz, DMSO-ab) 5 5.34 (5, 2H), 7.15 (40, 92.1 Hz, 1), 7.30-7.54 (t, bH), 7.62 (5, 2H). 196 NMR (282 MHz, dimethylsulfoxide-4b) b -66.0 (s, 1). MO-IER t/2 calc. 282.0474, found 283.1 (Ma) k; retention time: 1.75 min. (Method RH I).

Stage 5: tert-butyl (45)-4-IZ3-K4-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethyl-pyrrolidine-1-carboxylate (9) o --

MN, oo (o) ON X and

Vos-mM no ku what

ON X and MN

M

E about

tert-butyl (45)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (312 mg, 1.217 mmol), 4-benzyloxy-6-fluoro - pyridine-2-sulfonamide (344 mg, 1.219 mmol), anhydrous dimethylsulfoxide (3.5 ml) and diisopropylethylamine (0.32 ml, 1.837 mmol). The vial was closed and stirred at 857 for 16 h. The mixture was diluted with ethyl acetate (50 ml), water (50 ml) and 10 95 citric acid (10 ml). The two phases were separated. The organic phase was washed with saline solution (30 ml),

dried over sodium sulfate, filtered and the solvents evaporated. The product was purified by silica gel chromatography using a gradient of ethyl acetate (0 95 to 70 95 over 30 min) in hexane to give tert-butyl (45)-4-IZ3-K4-benzyloxy-6-sulfamoyl-2-pyridyl)amino| propyl|-2,2-dimethylpyrrolidine-1-carboxylate (427 mg, 68 95) as a white foamy solid. 1H NMR (400 MHz, DMSOO-ab) b 7.47 - 7.29 (t, 5H), 7.07 (5, 2H), 6.83 (I, U - 5.4

Gu, 1H), 6.66 (y, U - 2.0 Gu, 1H), 6.15 (a, U - 1.68 Hz, 1H), 5.14 (5, 2H), 3.55 (d, U - 9.5 Hz, 1H), 3.25 ( rgoas 4, u - 6.4 Hz, 2H), 2.78 (d, U - 9.9 Hz, 1H), 2.10 (Bg 5, 1H), 1.94 - 1.81 (t, 1H), 1.57 - 1.43 (t, 2H), 1.45 - 1.29 (t, 15Н), 1.24 (5, ЗН). MO-IER n/2 calc. 518.2563, found 519.4 (M--1)k; retention time: 1.92 min. (Method of RH B).

Stage b: tert-butyl /(45)-4-3-(4-benzyloxy-6-(2-chloro-6-13-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazole-1 -yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate oo (c) och --

Highway called soYao -U Mi sao, on M / w M ikh ) and MN i a: spe

To a stirred solution of /2-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (130 mg, 0.3613 mmol) in to anhydrous tetrahydrofuran (2 mL) was added carbonyldiimidazole (60 mg, 0.3700 mmol) and stirring was continued at ambient temperature under a nitrogen atmosphere for 2 hours. A solution of tert-butyl (45)-4-I3-K(4-benzyloxy-6-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (160 mg, 0, 3085 mmol) in anhydrous tetrahydrofuran (1 mL), followed by 1,8-diazabicyclo(/5.4.0)undec-7-ene (200 μL, 1.337 mmol), and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed under reduced pressure, and the residue was diluted with ethyl acetate (20 mL) and water (20 mL), and the mixture was slowly acidified with 4 M aqueous hydrochloric acid (350 μL of 4 M, 1,400 mmol) to about pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic phases were washed with saline (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (gradient from O 95 to 70905 ethyl acetate in hexane over 35 minutes) to give tert-butyl (45)-4-(3-((A-benzyloxy-6-(2-chloro- 6-|3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl)|sulfamoyl|-2-

From pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (72 mg, 27 95) as a white solid. MO-IER t/2 calc. 859.34937, found 860.6 (M.-1)w; retention time: 2.41 min. (Method of RH C).

Stage 7. M-(4-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I3-( 2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) o y and Z

From mm and Me: M hy

M | - and " MN uk M si MN

Dt M si -- - (v; a - s - ody

TEA

To the mixed solution tert-butyl (45)-4-I3-(4-benzyloxy-6-((2-chloro-6-I(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol- 1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (70 mg, 0.08135 mmol) in anhydrous methylene chloride (2 ml) was added trifluoroacetic acid (300 µL, 3.894 mmol) at ambient temperature under nitrogen. The orange solution was stirred for 1 h, then the volatiles were removed under reduced pressure. Toluene (20 mL) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and, finally, dried in a vacuum for 2 h to obtain crude /- M-(4-benzyloxy-6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl| sulfonyl|-2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1-

yl|pyridine-3-carboxamide (trifluoroacetate salt) (71 mg, 100 95). MO-IER tp/2 calc. 759.29694, found 760.5 (M.-1) k; retention time: 2.01 min. (Method of RH B).

Stage 8: (145)-21-(benzyloxy)-8-I3-(2-yldispiro(2.0.2.1|heptan-7-ilyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6 -thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione o (o) (c) o - ng 2 om - ng 5 / o s МН же МН 0-4 М М СИ -- -0 0-47 М -4 е -47 du

TRA

A 20 ml vial was loaded with M-((4-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2-chloro-6 -I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (67 mg, 0.07663 mmol), potassium carbonate (65 mg, 0 .4703 mmol), cesium fluoride (24 mg, 0.1580 mmol) and anhydrous dimethyl sulfoxide (5 ml) in the indicated order. The vessel was purged with a stream of nitrogen for 2 minutes, closed with a lid and stirred at 160 "C for 15 hours. The reaction mixture was given allowed to cool to ambient temperature, and the heterogeneous mixture was diluted with ethyl acetate (30 mL) and water (20 mL) and acidified with hydrochloric acid (1.0 mL, 1.0 M, 1.000 mmol). The layers were separated and the aqueous layer was re-extracted with ethyl acetate ( 20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (0 95-10 95 methanol in dichloromethane for 30 min), obtaining (145)-21-(benzyloxy)-8-|3-(2- ydispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl| -12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21- hexane-2,2,4-trione (34 mg, 61 95) as a white solid. MO-IER t/: calc. 723.3203, found 724.5 (Ma) k; retention time: 2.22 min. (method RH b).

Stage 9: (145)-8-I3-(2-idispiro|(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-21-hydroxy-12,12-dimethyl-2A6b -thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione ( compound 264) he (c) (c) o - hu m" Х ІІ | Id! M se " о Mi Mn

To a stirred solution (145)-21-(benzyloxy)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-ylylethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6- thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (25 mg, 0.03454 mmol) in anhydrous methanol (5 mL) was added 10 95 palladium on charcoal (wet,

Oediz5za, 12 mg, 0.01128 mmol) in a nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (balloon) for three hours. At ambient temperature. The hydrogen cylinder was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethylsulfoxide (1.5 mL) and filtered through a disc filter for a M/paytap syringe with

PTFE 0.45 μm. The sample was purified using a preparative reversed-phase HPLC-MS (column I ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art.: 00С-4252-00-АХ), (run with by a double gradient of 30 95-99 95 acetonitrile in water for 15 min (without modifier)| with obtaining (145)-8-I3-(2-idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazole - 1-yl|- 21-hydroxy-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose-1(23),5, 7,9,19,21-hexane-2,2,4-trione (compound 264) (8 mg, 36 95) as an off-white solid. 1H NMR (400 MHz, Meipapo!-a4) 6 8.24 ( a, y - 2.8 Hz, 1H), 7.85 (a, U - 8.2 Hz, 1H), 6.97 (a, U - 8.2 Hz, 1H), 6.75 (a, U - 1.9 Hz, 1H), 6.00 (y, U - 1.9 Hu, 1H), 5.94 (a, 9 - 2.7 Hu, 1H), 4.24 (I, U - 6.6 Hu, 2H), 4.02 (I, U - 13.1 Hz, 1H), 3.38 - 3.32

(t, 2H), 3.08 - 2.97 (t, 1H), 2.92 (Her, 9 - 10.5 Hz, 1H), 2.24 - 2.09 (t, 1H), 1.88 (ad, U - 6.6 Hz, ЗN), 1.85 - 1.76 (t, 1Н), 1.66 (5, ЗН), 1.63 (а, 9У - 5.7 Hz, 2Н), 1.60 (5, ЗН), 1.49 (а, 9 - 6.5 Hz, 1Н), 1.47 - 1.39 (t , 1H), 0.91 - 0.79 (t, 4H), 0.66 (ada, 9 - 8.8, 4.7, 3.4 Hz, 2H), 0.58 - 0.48 (t, 2H). MO-IER t/72 calc. 633.2733, found 634.5 (M'-1)k; retention time: 2.27 min. (Method of RH B).

Example 89: Preparation of (145)-21-hydroxy-12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 265) (9) (9) 5 he o / is M - u le "shchiE- MN -Oto nada; that

V y M- 5ier2 ss M- y ev ody o on ) (c) uh y

Te Y M- | te Y M- and Den kak Mn I, E uk Mi M MN

Stage 1: tert-butyl (45)-4-I3-(4-benzyloxy-6-C2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine- 3-carbonyl I sulfamoyl|-2-pyridyliamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate 5-9 7 7 I " Mn E M | - Y "t sh Mo 3-9 " Garden

To a stirred solution of 2-chloro-6-I3-I(3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (130 mg, 0.3335 mmol) in anhydrous tetrahydrofuran (2 ml) was added carbonyldiimidazole (55 mg, 0.3392 mmol) and stirring was continued at ambient temperature under a nitrogen atmosphere for 2 hours. A solution of tert-butyl (45)-4-I3-K(4-benzyloxy-6- sulfamoyl-2-pyridyl)amino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (150 mg, 0.2892 mmol) in anhydrous tetrahydrofuran (1 mL), then 1,8-diazabicyclo/5.4.01undec-7 -ene (200 μL, 1.337 mmol) and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed under reduced pressure, and the residue was diluted with ethyl acetate (20 mL) and water (20 mL), and the mixture was slowly acidified with 4 M aqueous hydrogen chloride acid (350 μL 4 M, 1.400 mmol) to about pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic phases were washed with brine aqueous solution (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (gradient from 095 to 70905 ethyl acetate in hexane

Zo for 35 minutes) to obtain tert-butyl (45)-4-I3-((4-benzyloxy-6 -(2-chloro-6-I(3-I3-H1- (trifluoromethyl)cyclopropyl|propoxy|pyrazole- 1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (128 mg, 5095) as a white solid. MO-IER t/2 calc. 889 ,3211, found 890.6 (M--1) t, retention time: 2.25 min (Method RH C).

Stage 2: M-(4-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2- pyridyl|sulfonyl|-2-chloro-6-I(3 -I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-

Z-carboxamide (trifluoroacetate salt) c) (c) and Ukh o oyu and a: LZY pa; in zh - Ma I I tn ot s ШІ e (in) and EE and Y k in MN

TRA

To the mixed solution tert-butyl 4-I3-(4-benzyloxy-6-Ce-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl| To sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (121 mg, 0.1359 mmol) in anhydrous methylene chloride (3 mL) was added trifluoroacetic acid (500 μL, 6.490 mmol) at ambient temperature in under a nitrogen atmosphere. The orange solution was stirred for 1 h, and then the volatiles were removed under reduced pressure. Toluene (20 mL) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and finally dried in vacuum for 2 h to obtain crude M-((4-benzyloxy-6-3-(35)-5,5-dimethylpyrrolidine-

Z-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (trifluoroacetate salt) (122 mg, 99,965). The material was carried directly to the next step without any purification. MO-IER n/2 calcd 789.2687, found 790.5 (M--1)k; retention time: 1.9 min. (Method RH B).

Stage C: (145)-21-(benzyloxy)-12,12-dimethyl-8-(3-(3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione o o o o o o

A 20 ml vial was loaded with M-((4-benzyloxy-6-I(3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2-chloro-6 -I3-I(3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (trifluoroacetate salt) (115 mg, 0.1272 mmol), potassium carbonate (110 mg, 0.7959 mmol), cesium fluoride (39 mg, 0.2567 mmol) and anhydrous dimethylsulfoxide (9 mL), in the indicated order. The vessel was purged

under a stream of nitrogen for 2 minutes, capped and stirred at 160 °C for 15 hours. The reaction mixture was allowed to cool to ambient temperature, and the heterogeneous mixture was diluted with ethyl acetate (40 mL) and water (30 mL) and acidified with hydrochloric acid (1, 6 mL of 1.0 M, 1.600 mmol). The layers were separated and the aqueous layer was re-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure The crude product was purified by chromatography on silica gel (gradient from

About 95 to 10 95 methanol in dichloromethane for 30 min), obtaining (145)-21-(benzyloxy)-12,12-dimethyl-8-(3-13-(1-(trifluoromethyl)cyclopropyl|propoxy)-1 N-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19( 23),20-hexane-2,2,4-trione (54 mg, 56 95) as a white solid. MO-IER Ip/2 calc. 753.29205, found 754.5 (M'1)-k; retention time: 1.51 min. (The method of RH U).

Stage 4: (145)-21-hydroxy-12,12-dimethyl-8-(3 13-/1-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9 .

o he (o) o o

Eh M y5 M i

N M | n M kozh 5-47 schi one No 5-47 schi od ed - ed -

To a stirred solution of (145)-21-(benzyloxy)-12,12-dimethyl-8-(3-13-|1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trione (40 mg, 0.05306 mmol) in anhydrous methanol (5 mL) was added with 10 95 palladium on charcoal (wet,

Oedivza, 19 mg, 0.01785 mmol) in a nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (balloon) for 2.5 hours. At ambient temperature. The hydrogen cylinder was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethylsulfoxide (1.5 mL) and filtered through a disc filter for a U/paytap syringe with

PTFE 0.45 μm. The sample was purified using a preparative reversed-phase HPLC-MS (column I ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art.: 00С-4252-Ц00-АЧ), (run with by a double gradient of 30-99 95 acetonitrile in water for 15 minutes (without modifier) | With obtaining (145)-21-hydroxy-12,12-dimethyl-8-(3-73-11-(trifluoromethyl)cyclopropyl|Ipropoxy)- 1 H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19 (23),20-hexane-2,2,4-trione (compound 265) (16 mg, 45 95) as a pale blue-green solid. 1H NMR (400 MHz,

Meipapo!-a4) b 8.25 (a, U - 2.68 Hu, 1H), 7.85 (a, 9 - 8.2 Hu, 1H), 6.97 (4.9 - 8.2 Hz, 1H), 6.76 (y, 9 - 1.9 Hz .

Gu, 1H), 3.36 - 3.32 (t, 1H), 3.02 (8, U - 13.6 Hz, 1H), 2.94 (I, U - 10.5 Hz, 1H), 2.24 - 2.08 (t, 1H), 1.94 (dd4 , y - 11.0, 6.3 Hz, 2H), 1.90 - 1.79 (t, 2H), 1.78 (а, У - 4.6 Hz, 1H), 1.77 - 1.74 (t, 1H), 1.66 (5, ЗН), 1.63 ( y, U - 7.0 Hz, 2H), 1.60 (5, ЗН), 1.58 (а, 9 - 7.9 Гу, 1Н), 1.51 - 1.36 (t, 1Н), 0.98 - 0.92 (t, 2Н), 0.73 - 0.65 (t, 2H). 196 NMR (376 MHz, methanol-a4) b -70.92. MO-IER t/2 calc. 663.24506, found 665.5 (M.-1)x; retention time: 2.13 min. (Method of RH B).

Example 90: Preparation of 2-imino-12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Abthia-3,9,11 ,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1, enantiomer 1) ( Compound 266), 2-imino-12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9 ,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1, enantiomer 2 ) (Compound 267), 2-imino-12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2А6b-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 2, enantiomer 1) (Compound 271) and 2-imino-12,12-dimethyl-8-(3-12-|(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia -3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (a pair of diastereomers 2, enantiomer 2) (Spo luka 272) o om oo mn o, MN dE U

M Sh | - iv vier1 Yam ve M iv y- yavod sadi " 7 t 7 im v o oh utro nie RO

Stage 1: 2-imino-12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9, 11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1, enantiomer 1) ( compound 266) and 2-imino-12,12-dimethyl-8-(3- (2-P-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Abthia-3,9,11 ,18,23-

pentaazatetracyclo!| 1 7.3.1.111,14.05,10)tetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1, enantiomer 2) (compound 267) о о ох" о om KU Fo i i pre seSte How cha ac a OR I

M / Fe Iv i Mshchi z Z ogle u

Racemic 2-imino-12,12-dimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21- hexane-2,4-dione (81 mg, 0.1248 mmol) (para diastereomers 1) (81 mg) were subjected to chiral NRC (Spiga!Rak A0-H (250 x 10 mm), 5 μM column; mobile phase 34 95 acetonitrile/methanol (50:50, 20 MM MNH), 66 95 carbon dioxide, 10 ml/min; concentration 12 mg/ml in acetonitrile/methanol (50:50 20 mM MNH); injection volume 70 μl, 100 bar) with 2-imino-12,12-dimethyl as the first eluted enantiomer -8-(3-2-1P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracycloyl!17.3.1.111,14.05, 10|tetracose- 1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 1, enantiomer 1) (Compound 266) (15.2 mg, 38 95), IN NMR (400 MHz, DMSOO-ab) 5 8.14 (a, 9 - 2.7 Gu, 1H), 7.75 (a, U - 8.1 Hz, 1H), 7.54 - 7.43 (t, 1H), 7.03, 9 - 6.8 Hz, 2H ), 6.77 (0.9 - 8.1 Hu, 1H), 6.54 (a, U - 8.4 Hz, 1H), 6.00 (a, U - 2.6 Hz, 1H), 4.24 (, U - 7.0 Hz, 2H), 3.17 (aa, U - 10.8, 7.3 Hz, 1H), 2.12 (5, 1H) , 2.05 - 1.99 (t, 2H), 1.82 (5, 2H), 1.53 (a, U - 26.0 Hz, 9H), 1.23 (8, U - 51.9 Hz, 4H), 0.85 (a, U - 28.0 Hz, 4H); MO-IER t/7 calc. 632.2505, found 633.0 (M--1)k; Retention time: 3.16 min (method RH B); and as the second eluted enantiomer 2-imino-12,12-dimethyl-8-(3-2-1P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9 . Compound 267) (15 mg, 38 90). 1 H NMR (400 MHz, dimethylsulfoxide-ab) b 8.21 (5, 1H), 7.82 (y, 9U - 8.1 Hz, 1H), 7.53 (5, 1H), 7.09 (5, 2H), 6.83 (0, U - 8.1 Hz, 1H), 6.60 (a, U - 8.3 Hz, 1H), 6.07 (5, 1H), 4.30 (5, 2H), 3.48 (5, 1H), 3.24 (5, 1H), 2.20 (5 , 1H), 2.07 (y, U - 14.1 Hz, 2H), 1.87 (5, 2H), 1.59 (y, U - 25.3 Hz, 8H), 1.35 (5, 1H), 1.23 (5, 2H), 0.92 (8, 9U - 27.7 Hz, 4H). MO-IER t/72 calc. 632.2505, found 633.0 (MA) k; Retention time: 3.18 min (method РХ 0).

Stage 2: 2-imino-12,12-dimethyl-8-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 2, enantiomer 1) (compound 271 ) and 2-imino-12,12-dimethyl-8-(3- (2-P-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)tetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 2, enantiomer 2) (compound 272) о ом о ох Se sia 0-5 koh Or and

Racemic 2-imino-12,12-dimethyl-8-(3-(2-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,4-dione (pair of diastereomers 2) (91 mg) was subjected to chiral NKRKH (Rpepotepeh I OX-4 (250 X 21.2 mm), column 5 μM; mobile phase 40 95 acetonitrile/methanol (90:10, 20 mM MNH), 6O 95 carbon dioxide, 70 ml/min; concentration 15 mg /ml in acetonitrile/methanol (90:10; 20 mM

MNH); injection volume 700 μl, 100 bar)". The first enantiomer was further eluted by reverse-phase preparative chromatography using a C18 column and 15 min. an eluent gradient from 50 95 to 99 9o acetonitrile in water containing 10 mM ammonium formate to give 2-imino-12,12-dimethyl-8-(3-12-(11-«"trifluoromethyl)cyclopropyl|ethoxy)- 1 H-pyrazol-1-yl)-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19, 21-hexane-2,4-dione (pair of diastereomers 2, enantiomer 1) (Compound 271) (22.4 mg, 50 95). IN NMR (400 MHz, DMSOO-ab) b 8.19 (y, U - 2.7 Hz . 9.5 Hz, 2H), 6.65 (y, U - 8.4 Hz, 1H), 4.31 (her, U - 7.0 Hz, 2H), 4.08 - 3.92 (t, 1H), 3.20 (5, 1H), 2.89 (y, U - 10.8 Hz, 2H), 2.08 (d, U - 7.0, 6.0 Hz, ZN), 1.86 - 1.72 (t, 2H), 1.55 (0, 9. - 27.1 Hz, TON), 1.31 (y, 9 - 11.4 Gu, 1H), 0.92 (y, 9 - 28.7 Hz, 5H). MO-IER t/7 calculated 632.2505, found 633.0 (M--1)4; retention time: 3.02 min. (Method LC 0) The second enantiomer eluted after HLC separation was 2-imino-12,12-dimethyl-8-(3-2-11-(trifluoromethyl)cyclopropyl|eth xy)-1H-pyrazol-1-yl)-2Abthia-3,9,11,18,23-

pentaazatetracyclo!| 1 7.3.1.111,14.05,10)tetracose-1(23),5,7,9,19,21-hexane-2,4-dione (para 2 diastereomer, enantiomer 2) (Compound 272) (29.8 mg , 67 90). 1 H NMR (400 MHz, dimethylsulfoxide-a 6) b 8.19 (y, 9 - 2.6 Hz, 1H), 7.93 (9.9 - 8.1 Hu, 1H), 7.60 - 7.52 (t, 1H), 7.41 (5, 2H), 7.05 (a, U - 7.2 Hz, 1H), 6.85 (aa, U - 12.7, 8.7 Hz, 2H), 6.64 (a, U - 8.4 Hz, 1H), 6.06 (a,

U 2.6 Hz, 1H), 4.31 (5, 2H), 3.99 (a, U - 11.5 Gu, 1H), 3.20 (5, 1H), 2.91 (a, 9U - 10.9 Hz, 2H), 2.08 (i,

U E 7.0 Hz, ZN), 1.88 - 1.71 (t, 2H), 1.55 (a, y - 27.0 Hz, 9H), 1.31 (a, U - 11.2 Gu, 1H), 0.92 (a, 9 2 29.2 Hz, 4H). MO-IER t/2 calc. 632.2505, found 633.0 (М-а-1)ж; Retention time: 3.07 min (method РХ 0).

Example 91: Preparation of (145)-12,12-dimethyl-8-(3-13-11-"(trifluoromethyl)cyclopropyl)|-3,3-dideutero-propoxy)-1H-pyrazol-1-yl) -2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10),6,8,19(23),20- hexane-2,2,4-trione (Compound 269) (9) now ro ro

ES ОН вер 1 pe zier2 pe zier Z ES вер 4 » он - - ОоМБ --- -Щжтщяж'k К) З -- - -5к кр зер 5 Дт зиверб д зивр7 ша зиер 8 о зивр 9 вод» я slo zier10 Di Vivre 11 zi i re wes bo wes bo si M si o 0) hoDyKe)

M - May 13

Kk shcha ZHK and VosM MN o oo h/Y so te (v

J ul. M SI -Ya | In and | In o. 5 January 15 - r M y vo (c) x17 zhk w- MN r ws o z r

Stage 1: dideutero-|1-(trifluoromethyl)cyclopropyl|methanol (c) what:

ОНО00-- фюЮ (РГс он

To a suspension of lithium aluminum deuteride (2.86 g, 71.563 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (10 g, 64.898 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 " C. The reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with diethyl ether (100 mL) and quenched with water (2.9 mL), sodium hydroxide (2.9 mL), and water (8.7 mL) successively at 0 "s.

The reaction mixture was stirred at room temperature for 30 min. The white solid was filtered through a pad of celite. The filtrate was concentrated under vacuum to give dideutero-|1-(trifluoromethyl)cyclopropyl|methanol (10.855 g, 86 90) as a clear liquid. 1H NMR (250 MHz, SOSIZ) b 1.72 (5, 1H), 1.03 (t, 2H), 0.79 (t, 2H).

Stage 2: Dideutero-(1-trifluoromethyl)cyclopropyl methyl methanesulfonate

Es --yu-y- Es on OM5

Zo

To a solution of didetero-|1-(trifluoromethyl)cyclopropyl|imethanol (8.537 g, 54.064 mmol) and triethylamine (10.942 g, 15.072 mL, 108.13 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (7.4318 g, 5.5 mL). 0215 mL, 64.877 mmol) dropwise at 0 "C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 95% citric acid (50 mL), saturated sodium bicarbonate (50 mL), and brine (50 mL). Organic the solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

P-trifluoromethyl)cyclopropyl|methyl|methanesulfonate (11.203 g, 88905) in the form of a clear liquid. TN NMR (250 MHz, SOSIZ) b 3.06 (5, ЗН), 1.21 (t, 2Н), 1.02 - 0.81 (t, 2Н).

Step 3: 2,2-didetero-2-(1-trifluoromethyl)cyclopropyl)|acetonitrile. ro, ro, o; --- F Yuk

OM5 p

Sodium cyanide (2.9296 g, 59.779 mmol) was added to a solution of (|didetero-|1-trifluoromethyl)cyclopropyl|methyl|methanesulfonate (11.203 g, 47.823 mmol) in dimethyl sulfoxide (55 mL).

The reaction mixture was stirred at 70 °C for 24 h. After cooling to room temperature, water (50 ml) and diethyl ether (50 ml) were added to the reaction mixture. The two layers were separated. The aqueous layer was extracted with diethyl ether (2 x 70 ml). the combined organic layers were washed with water (2 x 50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2,2-didetero-2-(1-(trifluoromethyl)cyclopropyl|acetonitrile ( 6.828 g, 84 Fo) as a yellow liquid. 1H NMR (250

MHz, SOSIZ) b 1.18 (t, 2H), 0.93 (5, 2H).

Stage 4: 2,2-didetero-2-(1-trifluoromethyl)cyclopropylacetic acid; ror; ek" - the same cr

KU

M

(6)

To a solution of 2,2-didetero-2-(/1-(trifluoromethyl)cyclopropyl|acetonitrile (6.828 g, 40.211 mmol) in CHNSO (70 mL) was added a solution of sodium deuteroxide (16.487 g, 40 wt/wt., 160 .84 mmol) in deuterium oxide (16 ml). The reaction mixture was stirred at 70 "C for 24 h. After cooling to room temperature, the SNH3S mass was removed under reduced pressure.

The solvent was diluted with water (70 ml) and washed with diethyl ether (2 x 50 ml). The aqueous layer was acidified to 6 n. hydrochloric acid to pH - 1, and then extracted with diethyl ether

Zo (3 x 70 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 2,2-didetero-2-(1-trifluoromethyl)cyclopropylacetic acid (6.387 g, 83 9o) in the form of a yellow liquid. TN NMR (250 MHz, SOSIZ) 56 1.18 - 1.05 (t, 2H), 0.93 - 0.79 (t, 2H).

Stage 5: 2,2-dideutero-2-(1-trifluoromethyl)cyclopropyl ethanol. yesterday ro kr dl - - o

A solution of 2,2-dideutero-2-(1-(trifluoromethyl)cyclopropyl|acetic acid (3, 35 g, 19297 mmol) in anhydrous tetrahydrofuran (50 ml) at 0 "C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with diethyl ether (50 ml) and cooled to 0 "C. Water (1 ml ), 15 95 aqueous sodium hydroxide (1 ml) and water (3 ml), and the resulting mixture was stirred at room temperature for 15 minutes. Anhydrous magnesium sulfate was added and the reaction mixture was stirred at room temperature for another 15 minutes.

The solids were filtered off and the filtrate was concentrated under vacuum to give 2,2-dideutero-2-I(1-trifluoromethyl)cyclopropyl ethanol (3.154 g, 8490) as a clear liquid. TN NMR (250 MHz, SOSIZ) b 3.79 (5, 2H), 1.05 - 0.78 (t, 2H), 0.78 - 0.41 (t, 2H).

Stage 6: (2,2-didetero-2-(1-trifluoromethyl)cyclopropyl|ethyl|methanesulfonate ro ro

Es on

K --shZhh di

To a solution of 2,2-didetero-2-|1-(trifluoromethyl)cyclopropyl|ethanol (3.154 g, 16.160 mmol) in dichloromethane (32 mL) was added triethylamine (4.9057 g, 6.7572 mL, 48.480 mmol). The reaction mixture was cooled to 0 "C and methanesulfonyl chloride (2.2214 g, 1.5009 mL, 19.392 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 days.

The reaction mixture was diluted with dichloromethane (50 mL) and washed with 10 95 aqueous citric acid (50 mL), saturated sodium bicarbonate (50 mL), and saturated saline (50 mL). The solution was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of 0 95 to 50 90 diethyl ether in hexane to give (2,2-didetero-2-|1-(trifluoromethyl)cyclopropyl|IIethyl|methanesulfonate (3.28 g, 82 95) in the form of a transparent liquid, 1N

NMR (250 MHz, SOSIZ) b 4.36 (5, 2H), 3.20 - 2.87 (5, ЗН), 1.15 - 0.94 (t, 2H), 0.79 - 0.59 (t, 2H).

Stage 7: 3,3-didetero-3-I/1-(trifluoromethyl)cyclopropyl|propanenitrile ro ro M di Kn ---

Sodium cyanide (858 mg, 16.6 mmol) was added to a solution of (|2,2-didetero-2-|/1-(trifluoromethyl)cyclopropyl|ethyl|methanesulfonate (3.28 g, 13.303 mmol) in dimethyl sulfoxide (17 mL) ).

The reaction mixture was stirred at 70 "C for 16 h. After cooling to room temperature, the reaction mixture was poured into water (30 ml). The mixture was extracted with diethyl ether (3 x 50 ml). The combined organic layers were washed with water (2 x 30 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 3,3-didetero-3-(1-trifluoromethyl)cyclopropyl|propanenitrile (2.267 g, 99 90) as a clear liquid . IN NMR (250 MHz, SOSIZ) b 2.54 (5, 2H), 1.14 - 1.00 (t, 2H), 0.80 - 0.66 (t, 2H).

Stage 8: 3,3-didetero-3-|/1-trifluoromethyl)cyclopropyl|propanoic acid.

EM

Kn same vd on

To a solution of 3,3-didetero-3-(1-trifluoromethyl)cyclopropyl|ipropanenitrile (2.267 g, 13.178 mmol) in ethanol (34 mL) was added a solution of sodium hydroxide (2.1083 g, 52.712 mmol) in water (9

From ml ). The reaction mixture was stirred at 70 "C for 20 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum, then diluted with water (30 ml).

The aqueous solution was washed with diethyl ether (2 x 30 ml), and then it was acidified with 6 N. with hydrochloric acid (aqueous) to pH - 1. The aqueous solution was extracted with diethyl ether (3 x 50 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give

3,3-Dideutero-3-(1-trifluoromethyl)cyclopropyl|Ipropanoic acid (2.652 g, 92 905) in the form of a light yellow liquid. 1H NMR (250 MHz, SOSIZ) 6 2.55 (5, 2H), 1.07 - 0.82 (t, 2H), 0.61 (t, 2H).

Stage 9: 3,3-didetero-3-|/1-«"trifluoromethyl)cyclopropyl|propan-1-ol ro ro

Es

To a suspension of lithium aluminum hydride (628 mg, 14.940 mmol) in anhydrous tetrahydrofuran (20 mL) was added a solution of 3,3-didetero-3-(1-(trifluoromethyl)cyclopropyl|propanoic acid (2.652 g, 12.097 mmol) in anhydrous tetrahydrofuran (20 ml) at 0 "C dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with diethyl ether (20 ml) and cooled to 0 "C. Water (0.63 ml), 1595 aqueous sodium hydroxide (0.63 mL) and water (1.9 mL). The reaction mixture was stirred at room temperature for 15 minutes, then magnesium sulfate was added and the reaction mixture was stirred for another 15 minutes at room temperature. The white precipitate was filtered off. The filtrate was concentrated at reduced pressure to obtain 3,3-dideutero-3-

P-trifluoromethyl)cyclopropyl|Ipropan-1-ol (1.78 g, 82 95) in the form of a clear liquid. TIA NMR (250 MHz, DMSO-ab) 5 4.45 (I, 9) - 5.1 Hz, 1H), 3.46 - 3.36 (t, 2H), 1.50 (I, U - 6.2 Hz, 2H), 0.86 (t, 2H ), 0.69 (t, 2H).

Stage 10: tert-butyl 3-IZ,3-dideutero-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate)

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (910 mg, 4.940 mmol) and 3,3-dideutero-3-(1-trifluoromethyl)cyclopropyl|Ipropan-1-ol (880 mg , 5.171 mmol) in tetrahydrofuran (11.25 mL) was added triphenylphosphine (1.36 g, 5.185 mmol). Diisopropylazodicarboxylate (1.05 g, 5.193 mmol) was slowly added dropwise to the mixture over 5 minutes.

The reaction mixture was stirred at room temperature for 30 min. Tetrahydrofuran was removed by oil. The crude product was purified by silica gel chromatography using a shallow gradient from 100 95 hexane to 20 95 ethyl acetate in hexane to give tert-butyl-3-

3,3-dideutero-3-(/1-(trifluoromethyl)cyclopropyl|propoxy)pyrazole-1-carboxylate (1.1 g, 66 95) as a colorless oil. IN NMR (400 MHz, Spiogothogite-a) b 7.83 (a, Y - 3.0 Hz, 1H), 5.85 (j, y - 3.0

Hz, 1H),4.27 (4.9 -6.2 Hu, 2H), 1.90 (I, 7 - 6.4 Hu, 2H), 1.61 (5, 9H), 1.00 - 0.91 (t, 2H), 0.64 - 0.50 (t , U - 1.6 Hz, 2H). MO-IER tp/2 calc. 336.163, found 337.2 (M--1)k; Holding time: 2.03 min. (Method of RH E).

Stage 11: 3-3,3-dideutero-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|-1H-pyrazole

M.M. and MVos. and MN

B shi 0 -- HOW -

B s r r s V r

To a flask containing tert-butyl-3-3,3-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1-carboxylate (1.1 g, 3.270 mmol) was added dichloromethane (22 mL) and trifluoroacetic acid (6.3 ml, 81.77 mmol). After 30 min, the mixture was evaporated to dryness and neutralized with saturated aqueous sodium bicarbonate. Reaction mixture

Zo was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered and evaporated to give 3-3,3-didetero-3-(/1-(trifluoromethyl)cyclopropyl|propoxy|-1H-pyrazole (762 mg, 99 95) in the form of a colorless oil. MO-IER p/2 calc. 236.11055, found 237.2 (MA) k; Retention time: 1.43 min (Method RH E).

Stage 12: tert-butyl 2-chloro-6-13-3,-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate c) (o) xu c

In t re Mo uva - | - t - M si

Z si MU oi Z shchve Bo ve?

tert-butyl 2,6-dichloropyridine-3-carboxylate (800 mg, 3.224 mmol), 3-3,3-dideutero-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|-1H-pyrazole (762 mg, 3.226 mmol) and potassium carbonate (1.1 g, 7.959 mmol) were combined in anhydrous dimethyl sulfoxide (22.0 mL). 1,4-diazabicyclo(2.2.2|octane (72.5 mg, 0.463 mmol) was added and a mixture stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with water (16 mL) and stirred for 15 min. The solid formed was filtered, collected, and dried under high vacuum. The remaining filtrate was diluted with ethyl acetate and washed with water (3 x 20 mL ). The organic layers were combined and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 100 95 hexanes to 60 95 ethyl acetate in hexane to give a light -yellow oil, which was then dried in a vacuum, obtaining pale yellow solid substance This purified solid and the solid after initial filtration were combined to give tert-butyl-2-chloro-6-(3-N3,3-dideutero-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1- yl|pyridine-3Z-carboxylate (1.36 g, 94 90).IN NMR (400 MHz, Spiogytogt-a) b 8.35 (y, 9 - 2.8 Hz, 1H), 8.18 (a, Y - 68.4 Hu, 1H ), 7.68 (a, U - 8.4 Hz, 1H), 5.95 (j, U - 2.8 Hz, 1H), 4.2641.9 - 6.2 Hz, 2H), 1.9541.9 - 6.2 Hz, 2H), 1.62 (5, 9H), 1.02 - 0.94 (t, 2H), 0.66 - 0.55 (t, U - 1.8 Hu, 2H). MO-IER t/:2 calc. 447.15054, found 448.2 (M--T) flat; Holding time: 2.49 min. (Method of RH E).

Stage 13: 2-chloro-6-N3-3,3-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid

M

Tert-butyl-2-chloro-6-13-33,3-dideutero-3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (1.36 g, 3.037 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (5.0 mL, 64.90 mmol) was slowly added to the mixture and the mixture was continued to stir at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to a solid, which was then suspended in diethyl ether and filtered, then the solid was resuspended in diethyl ether and filtered to give a solid, which was recrystallized from dichloromethane, then dried in vacuo for 20 h to give 2- chloro-6-13-33,3-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (1.055 g, 89 95) as a white solid. MO-IER t/2 calc. 391.08795, found 392.2 (M--1); Holding time: 1.35 min. (Method of RH E).

Stage 14: tert-butyl (45)-4-I3-C(6-C2-chloro-6-I3-I3,3-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl) pyridine-3-carbonyl|!sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Ge) KYA 9) vy ra z

2-chloro-6-I3-IZ,3-didetero-3-(I1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl| pyridine-

3-carboxylic acid (250 mg, 0.6381 mmol) and freshly recrystallized carbonyldiimidazole (120

Zo mg, 0.7401 mmol) were combined in tetrahydrofuran (6.0 ml) and stirred for 2 hours at room temperature. Then tert-butyl (45)-2,2-dimethyl-4-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (303 mg, 0.7345 mmol) was added followed by of anhydrous 1,8-diazabicyclo/5.4.0)undec-7-ene (240 μl, 1.605 mmol), and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and then with saline. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient from 100 95 hexane to 100 95 ethyl acetate to give tert-butyl (45)-4-I3-C(6-C2-chloro -6-(3-IZ,Z-dideutero-3-

P-«(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridine-3--carbonyl|Isulfamoyl|-2- pyridylIamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (259 mg, 52 95) in in the form of a white solid. MO-IER t/2 calc. 785.2918, found 786.2 (M.-1)xzh; Holding time: 2.06 min. (Way

RK E).

Stage 15: (145)-12,12-dimethyl-8-(3-13-11-"trifluoromethyl)cyclopropyl|-3,3-dideteropropoxy)-1H-pyrazol-1-yl)-2A6-thia -3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5(10),6,68,19(23),20-hexane-2, 2,4-trione (Compound 269)

9) M (o) ohm/y

AND

M ---3-

Z dsh- os Mn Z dsh- MN vs o r HL III E cv;

Tert-butyl (45)-4-I3-(6-((2-chloro-6-I3-I(3,3-didetero-3-(1- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl| pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (228 mg, 0.2900 mmol) was dissolved in dichloromethane (/ ml) and trifluoroacetic acid (900 μl , 11.68 mmol) and stirred at room temperature for 15 minutes. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous saturated sodium bicarbonate (10 mL) was added. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The resulting material was combined with potassium carbonate (205 mg, 1.483 mmol), molecular sieves ZA, and dimethyl sulfoxide (9 .5 ml) in the vial was purged with nitrogen, closed with a lid, heated to 15072 and stirred for 16 hours. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with water (2 x 20 ml), and then with saline. The organic layer was additionally washed with water (their), then dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of 100 95 hexanes to 10095 ethyl acetate followed by a second column chromatography on silica gel using a gradient of 100 95 dichloromethane to 1095 methanol in dichloromethane to give (145)-12,12-dimethyl /8- (3-73-11-(trifluoromethyl)cyclopropyl|-3,3-dideteropropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3. 1.111,14.05,10)tetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (Compound 269) (44.8 mg, 24 9b5 ) in the form of a white solid. 1H NMR (400 MHz, DMSO-4a6) b 12.51 (5, 1H), 8.21 (a, 9U - 2.8 Hz, 1H), 7.81 (a, 9 - 8.3 Hz, 1H), 7.57 (Y, U - 7.9 Gu , 1H), 7.054549, 2: 7.2

Gu, 1H), 6.98 (5, 1H), 6.91 (y, U - 8.2 Hz, 1H), 6.71 (a, U - 6.6 Hz, 1H), 6.12 (9, U - 2.8 Hz, 1H), 4.20 ( Her,

U 6.3 Hz, 2H), 3.92 (9, U - 12.0 Hz, 1H), 3.17 (y, U - 5.2 Hu, 1H), 2.95 (a, U - 13.3 Hu, 1H), 2.69 (a, U - 15.6 Hu, 1H), 2.10 (a, U - 18.7 Hu, 1H), 1.83, U - 6.2 Hz, ZN), 1.79 - 1.69 (t, 1H), 1.60 (5, AN), 1.57 (a, 9U - 12.5 Hz, 2H), 1.51 (5, ZN), 1.37 - 1.22 (t, 2H), 0.93 - 0.89 (t, 2H), 0.75 (I, U - 1.6 Hz, 2H). MO-IER t/: calc. 649.2627, found 650.2 (M--1)f; retention time: 2.27 min. (The method of RH

IS).

From Example 92: Preparation of (145)-12,12-dimethyl-8-(3-13-11-"(trifluoromethyl)cyclopropyl)|-2,2-dideutero-propoxy)-1H-pyrazol-1-yl )-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane- 2,2,4-trione (Compound 270) ih (in; in r or

Z I 5 BK o zier 1 OH vera 5 O vivrz still vivr 4

E E E

IS

EE EE dz dya c); he r V he o u H ra v; zier 5 and U o vier 6 V o o already o viver 7 o t, nM--M - and E EE -y and more

(o) ra , "Zh o o U 9, ra m. | - ro lvva, ss 5ier 8 i Msi. NM OVC,

GU si M si E o eE E U (c) odi e)

M xx m o I still s h v ave sya li o i o - ver 10 o We Mach ---i- (c) 4 nm va - 377,

E (c) kl M E dat EE KE

Stage 1: 1,1-didetero-2-(1-trifluoromethyl)cyclopropyl|ethanol. o r r on on ----

E E

E E E E

To a suspension of lithium aluminum deuteride (1.0265 g, 25684 mmol) in anhydrous tetrahydrofuran (50 mL) was added a solution of 2-(/1-(trifluoromethyl)cyclopropyl|acetic acid (3.954 g, 19.757 mmol) in anhydrous tetrahydrofuran (50 mL) ) dropwise at 0 "C. The reaction mixture was stirred at room temperature for an additional 16 h. The reaction mixture was diluted with diethyl ether (50 ml) and cooled to 0 "C. Water (1 ml), 15 90 sodium hydroxide ( aqueous) (1 ml) and water (3 ml) at 0 "C. The reaction mixture was stirred at room temperature for 15 min. Anhydrous magnesium sulfate was added to the reaction mixture. The reaction mixture was stirred for another 15 min. The white precipitate was removed by filtration with suction and the solvent was removed under reduced pressure to obtain 1,1-dideutero-2-(1-(trifluoromethyl)cyclopropyl|ethanol (3.629 g, 82 95) in the form of a light yellow oil. TN NMR (250

MHz, chloroform-a) 6 1.83 (s, 2H), 1.43 (s, 1H), 1.04--0.91 (m, 2H), 0.72-0.62 (m, 2H ).

Stage 2: 1,1-didetero-2-(1-trifluoromethyl)cyclopropyl ethyl imethanesulfonate

OH (c) (c) ----

E E

E is b

Triethylamine (4.9388 g, 6.8028 mL, 48.807 mmol) was added to a solution of 1,1-didetero-2-(/1-trifluoromethyl)cyclopropyl ethanol (3.629 g, 16.269 mmol) in dichloromethane (36 mL). The mixture was cooled to 0 "C. Methanesulfonyl chloride (2.2364 g, 1.5111 mL, 19.523 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 10 95 aqueous citric acid solution (30 mL), saturated aqueous sodium bicarbonate solution (30 mL), and brine (30 mL). The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using gradient from 0 95 to 70 95 diethyl ether in hexane to give |1,1-dideutero-2-(1-trifluoromethyl)cyclopropyl|ethyl|methanesulfonate (3.413 g, 90 95) in the form of a clear liquid. IN NMR (250 MHz, chloroform-a) 6 3.02 (s, 3H), 2.02 (s, 2H), 1.14-0.95 (m, 2H), 0.81-0.63 (m, 2H) .

Zo Stage 3: 2,2-dideutero-3-/1-(trifluoromethyl)cyclopropyl|propanenitrile p/x o o o 5--M

E --- E

Ee Ee

Sodium cyanide (892.62 mg, 18.214 mmol) was added to a solution of (P1,1-didetero-2-I1-trifluoromethyl)cyclopropyl|ethyl|methanesulfonate (3.413 g, 14.571 mmol) in dimethyl sulfoxide (17 mL).

The reaction mixture was stirred at 70 "C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (30 ml) and extracted with diethyl ether (3 x 30 ml). The combined organic layers were washed with water (2 x 30 ml) and brine solution (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by chromatography on silica gel using a gradient of 0 95 to 50 95 diethyl ether in pentane to give 2,2-dideutero-3-/1- (trifluoromethyl)cyclopropyl|ipropanenitrile (2.181 g, 81 95) as a clear liquid.IN NMR (250 MHz, chloroform-a) b 1.92 (s, 2H), 1.14-1.01 (m, 2H) , 0.74 (m, 2H).

Stage 4: 2,2-didetero-3-|/1-«"trifluoromethyl)cyclopropyl|propanoic acid. в; р р р он -5В-М ----3353- --

E E (in)

Ee Ee

O20 (4 ml) and sodium deuteroxide in O20 (4.8191 g, 40 Fo by mass, 47.012 mmol). The reaction mixture was stirred at 70°C for 20 hours.

SNZSmagete was removed under reduced pressure. The resulting solution was diluted with 020 (20 ml) and washed with diethyl ether (2 x 20 ml). Then the aqueous solution was acidified to 6 N. with hydrochloric acid to pH - 1, then extracted with diethyl ether (3 x 20 ml).

The combined organic layers were washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2,2-dideutero-3-(1-trifluoromethyl)cyclopropyl propanoic acid (1.945 g , 8990) in the form of an amber liquid. 1H NMR (250 MHz, chloroform-4) b 1.89 (s, 2H), 1.10-0.88 (m, 2H), 0.75-0.52 (m , 2H).

Stage 5: 2,2-didetero-3-|/1-«"trifluoromethyl)cyclopropyl|propan-1-ol c) p OH oon ----i3-

E E E E

To a suspension of lithium aluminum hydride (521.15 mg, 0.5683 mL, 13.731 mmol) in anhydrous tetrahydrofuran (20 mL) a solution of 2,2-dideutero-3-(1-(trifluoromethyl)cyclopropyl|ipropanoic acid (1.945 g) was added dropwise. , 10.562 mmol) in tetrahydrofuran (20

3 ml) at 0 "C. The reaction mixture was stirred at room temperature for 16 hours.

The reaction was diluted with diethyl ether (30 mL) and quenched with water (0.53 mL), 1595 aqueous sodium hydroxide solution (0.53 mL), and water (1.59 mL) at 0 "C. The reaction mixture was stirred at room temperature for 30 minutes, and then anhydrous magnesium sulfate was added and stirred for another 15 minutes. The solid was filtered off and the filtrate was concentrated in vacuo to give 2,2-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propan-1-ol (1.423 g, 75 U) in the form of a transparent liquid. IN NMR (250 MHz, DMSO-4a6) b 4.44 (1, 2) - 5.1 Hu, 1H), 3.38 (5, 2H), 1.57 (5, 2H), 0.87 (I, In - 5.68 Hz, 2H), 0.69 (5, 2H).

Stage 6: tert-butyl 3-(2,2-dideutero-3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate p

Ge) M du - pad nM--m - 5th poh o

J

Oh my god

To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (775 mg, 4.208 mmol) and 2,2-dideutero-3-(1-trifluoromethyl)cyclopropyl|Ipropan-y-ol (750 mg, 4.407 mmol) in tetrahydrofuran (10 ml) was added triphenylphosphine (1.156 g, 4.407 mmol). Diisopropylazodicarboxylate (870 μl, 4.419 mmol) was slowly added dropwise to the mixture over 10 min.

The reaction mixture was stirred at room temperature for 30 minutes, then at 50 C for 30 minutes. The tetrahydrofuran was removed and the residue was purified by silica gel chromatography using a shallow gradient of 100 95 hexanes to 20 95 ethyl acetate in hexane to give tert-butyl-3-(2,2-didetero-3-|1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole -II-carboxylate (0.998 g, 7195) in the form of a colorless oil. "IN NMR (400 MHz, Spiogoitogit-4) b 7.83 (a, y - 2.9 Hz, 1H), 5.85 (a, y - 2.9 Hz, 1H) . found 337.2 (M--1) k, retention time: 1.96 min (Method RH B).

Stage 7: 3-(2,2-didetero-3-(11-(trifluoromethyl)cyclopropyl|propoxy|-1H-pyrazole c) |c)

W o c (c) r o M t hi-i t U mn dn (c) Uh "UN-

E E b EE

Dichloromethane (20 mL) was added to a round-bottom flask containing tert-butyl-3-(2,2-didetero-3-|11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate (998 mg, 2.967 mmol) and trifluoroacetic acid (5.7 mL, 73.98 mmol). After 5 min, the reaction mixture was evaporated to dryness and neutralized with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and evaporated to obtain 3-(2 ,2-didetero-3-(/1-(trifluoromethyl)cyclopropyl|Ipropoxy|-1H-pyrazole (700 mg, 100 95) in the form of a colorless oil. 1H NMR (400 MHz, Spiogoitogit-4) b 7.36 (a, 9 - 2.6 Gu, 1H), 5.73 (a, U - 2.5 Hz, 1H), 4.13 (a, U - 1.6 Hz, 2H), 1.72 (5, 2H), 0.99 - 0.93 (t, 2H), 0.63 - 0.56 (t, 2H). MO-IER t/2 calc. 236.11055, found 237.1 (M-a-1)g; Retention time: 1.41 min. (Method RH B).

Stage 8: tert-butyl 2-chloro-6-3-(2,2-didetero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (9) ; ! th r Ge) ul Zh M / Fe p N | oh oh with" in? -47 M Gei) and si M in ved - and E

Yev

A mixture of 3-(2,2-didetero-3-/1-(trifluoromethyl)cyclopropyl|propoxy|-1H-pyrazole (700 mg,

Zo 2.963 mmol), tert-butyl 2,6-dichloropyridine-Z-carboxylate (742 mg, 2.991 mmol), potassium carbonate (501 mg, 3.625 mmol) and 1,4-diazabicyclo|2.2.2)octane (71 mg, 0.330 mmol) in dimethylsulfoxide (5 ml) was stirred at room temperature for 15 hours.

The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saline, dried over sodium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on silica gel with a gradient from 100 95 hexane to 20 95 ethyl acetate in hexane to obtain tert-butyl /2-chloro-6-13-(2,2-dideutero-3-(11-(trifluoromethyl)cyclopropyl|propoxy |pyrazol-1-yl|pyridine-Z-carboxylate (472 mg, 3695) as a white solid. 1H NMR (400 MHz, Spiogotogpt-c4) b 8.35 (a, 9 - 2.8 Hz, 1H), 8.18 (a . , 9H), 1.02 - 0.94 (t, 2H), 0.63 - 0.57 (t, 2H). MO-IER t/2 calc. 447.15054, found 448.23 (Ma1)-; Retention time: 0.95 min. (Method RH A ).

Stage 9: tert-butyl (45)-4-I3-C(6-Ce-chloro-6-I3-(2,2-didetero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl |pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

B Y Ky kor Ouse KE peni miy mor V o - si H

E them E on x, on shi: F )f:

A solution of tert-butyl 2-chloro-6-3-(2,2-dideutero-3-|1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (250 mg, 0.5582 mmol ) in dichloromethane (1.5 mL) and trifluoroacetic acid (500 μL, 6.490 mmol) were stirred at room temperature for 4 h. The solvents were then removed and the residue dried in vacuo. The resulting residue was dissolved in tetrahydrofuran (2 mL) and carbonyldiimidazole (102 mg, 0.6291 mmol), and the mixture was stirred for 2 hours at room temperature. Tert-butyl (45)-2,2-dimethyl-4-13-((b-sulfamoyl-2-pyridyl)amino|propyl) was then added |pyrrolidine-1-carboxylate (255 mg, 0.6181 mmol) followed by the addition of 1,68-diazabicyclo|5.4.Fundec-7-ene (130 μl, 0.8693 mmol) and the reaction mixture was stirred for 16 hours. diluted with ethyl acetate and washed with a small amount of saturated aqueous ammonium chloride/brine 171. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl (45)-4-(3-((6-Ce-chloro-6-I3-(2,2- dideutero-3-(1- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (172 mg, 39 95) in the form of a white solid. MO-IER t/: calc. 785.2918, found 786.4 (M--1) same; retention time: 0.93 min. (Way

RH A).

Stage 10: (145)-12,12-dimethyl-8-(3-13-11-"trifluoromethyl)cyclopropyl)|-2,2-dideteropropoxy)-1H-pyrazol-1-yl)-2A6- thia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10)tetracose-1(23),5(10),6,8,19,21-hexane-2,2, 4-trione (Compound 270) (c) 5 ru I

Mem M mA and | and x a

In o -k si M m r yo - NM z» or ? - m Z, -- Mn

E - (c) water

E. M. E

In the class

Solution of tert-butyl (45)-4-I3-((6-Ce-chloro-6-(3-(2,2-didetero-3-11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine) -3-carbonyl|sulfamoyl|-2-

Zo pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (170 mg, 0.2162 mmol) in dichloromethane (1.2 mL) and trifluoroacetic acid (400 μL, 5.227 mmol) were stirred at room temperature for 4 h. Then the solvents were removed and the residue was dissolved in ethyl acetate. The mixture was washed with 2 ml of saturated sodium bicarbonate solution, the organic layer was collected and the solvent was removed in vacuo. The resulting residue was dissolved in dimethylsulfoxide (8 ml), molecular sieves Z A were added, and the reaction mixture was stirred for 10 min. Cesium fluoride (101 mg, 0.6649 mmol) and potassium carbonate (96 mg, 0.6946 mmol) were then added, and the reaction mixture was heated at 150 °C for 16 hours. ), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 30 95 to 99 95 mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile ) to obtain (145)-12,12-dimethyl-8-(3-13-11-(trifluoromethyl)cyclopropyl)|-2,2-dideuteropropoxy)-1H-pyrazol-1-yl)-2A6- thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2, 4-trione

(compound 270) (62.4 mg, 44 95) as an off-white solid. TIA NMR (400 MHz,

SNiogoitogt-a) b 9.87 (5, 1H), 8.19 (a, U - 2.68 Hz, 1H), 8.04 (y, 9 - 8.3 Hz, 1H), 7.56 - 7.44 (t, 2H), 7.23 (a, U - 8.4 Hu, 1), 6.55 (aa, U - 8.2, 1.0 Hu, 1H), 5.91 (a, U - 2.8 Hz, 1H), 4.71 (aa, U - 8.6, 3.4

Hz, 1H), 4.24 (5, 2H), 3.89 (5, 1H), 3.33 (49, U - 10.1, 7.4 Hz, 1H), 3.15 (yes, U - 14.0, 3.6 Hz, 1H), 3.05 (I , U - 9.8 Hz, 1H), 2.56 (5, 1H), 2.06 (ai, U - 12.2, 7.7 Hz, 1H), 1.74 (5, 2H), 1.61 (I, U - 4.0 Hz, TON), 1.01 - 0.93 (t, 2H), 0.64 - 0.57 (t, 2H). MO-IER tp/2 calc. 649.2627, found 650.12 (Ma) k;

Holding time: 1.75 min. (The method of RH (b).

Example 93: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-di(trideutero)methyl-2A6 -thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexaene-2,2,4- trionu (compound 274) (9) o o o eri Tov, ver? ro. Yam o vier3z ryu zir 4

MO res on r on what in v oti otu ot ves nm verb os M zivrv 0 M zer? ryu M zier8 o KD dv o shchi uh oo o z - M ! So Y M o nd 7 September 9 0-І MM si nd U a I «A A res MN, res MA

I HAVE MORE

M. - M m - M. y M y i-Y m SI vivr 11 5-4 M si vier12 m uv I r

Sh t u

Stage 1: 3-IZ,3,3-trideutero-2-nitro-2-trideuteromethyl)propyl|tetrahydropyran-2-one (c) (c) Co, (c) Co, ------.: .at

MO, 1,68-diazabicyclo/5.4.O01undec-7-ene (7.7 mL, 51.3 mmol) was added to a mixture of 1,1,1,3,3,3-hexadeutero-2-nitropropane (SOM Isoiore5, Quebec, Canada) (23.4 g, 246.2 mmol) and 3-methylenetetrahydropyran-2-one (23.0 g, 205.2 mmol). The reaction was exothermic: after the initial heat release dissipated, the mixture was heated in an oil bath at 80 "C for 18 hours, then cooled to room temperature and diluted with 1M hydrochloric acid (100 mL) and dichloromethane (500 mL). The phases were separated. The aqueous phase was discarded, and the organic phase was dried over sodium sulfate, filtered, and concentrated in massio to give 3-

3,3-trideutero-2-nitro-2-(trideuteromethyl)propyltetrahydropyran-2-one (41.8 g, 98905) as a yellow oil. The material was used at the next stage without additional purification.

MO-ER t/2 calc. 207.22, found 208.10 (M--1)k; Holding time: 3.29 min. (Method РХ 0).

Stage 2: 3-(3-hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one

(c) co, o

She and 5

Mo, r.s. on

A suspension of Raney nickel (5 g, 85 mmol) in water (10 mL) was added to a solution of 3-I3,3,3-trideutero-2-nitro-2-(trideuteromethyl)propylItetrahydropyran-2-one (41.8 g, 201 .8 mmol) in ethanol (600 ml). The resulting suspension was hydrogenated under H2 pressure of 60 lb/sq. inch at 80 "C for 22 hours, cooled to room temperature, filtered through Celite and then concentrated in vacuo to give an orange oil. The orange oil was purified by chromatography on silica gel (0-50 95 ethyl acetate in hexane gradient) to give pure 3-(Z -hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one (7 g, 20 95) as an off-white solid. 1H NMR (250 MHz, DMSO-ab) b 7.62 (5, 1H), 4.39 (y, 1H), 3.81 (t, 2H), 2.37 (t, 10. 2H), 2.01 (da, 1H), 1.73 (t, 1H), 1.43 (t, ЗН), 1.17 (t, 1H) MO-IER t/; calculated 177.20, found 178.00 (M.-1)k; Retention time: 1.91 min (Method RH O).

Stage 3: (35)-3-(3-Hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one

Ge) (c) all NM o, cheek r.s on r.s on

Racemic 3-(3-hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one (6.78 g) was subjected to chiral separation by NKR chromatography using SpigaIRak IA (column 250 0 X 21.2 mm, particle size 5 μm) with a mobile phase of 1095 methanol (no modifier)/90 95 carbon dioxide at 70 mL/min for 7.0 min (injection volume - 500 μL of a 32 mg/mL solution in methanol), obtaining as the first of the eluted enantiomer (35)-3-(3-hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one (2.4 g, 70.7 95) as an off-white solid. MO-IER t/: calc. 177.20, found 178.00 (M'-1)k; retention time: 1.91 min. (Method of RH B).

Stage 4: 3-((35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|Ipropan-1-ol (6) bis НМ ою НМ р-с он р.с он

Solid (35)-3-(3-hydroxypropyl)-5,5-bis (trideuteromethyl)pyrrolidin-2-one (2.4 g, 13.54 mmol) in portions over 20 min. During the addition, the internal temperature was maintained below 32 °C. The reaction mixture was then heated under reflux and stirred under a nitrogen atmosphere. After 19 h, the reaction mixture thickened and was no longer stirred. The reaction mixture was cooled to

From room temperature. Tetrahydrofuran (10 mL) and methyl tert-butyl ether (10 mL) were added to the mixture, followed by the dropwise addition of saturated sodium sulfate (aqueous) until no more bubbles formed. Another 10 ml of saturated sodium sulfate solution was added to the cloudy solution. The mixture was filtered through celite and washed with methyl tert-butyl ether. The filtrate was concentrated to give 3-(35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|propan-1-ol (1.85 g, 83 Fo) as a clear oil. 1H NMR (400

MHz, DMSO-ab) b 4.32 (y, 9) - 5.2 Hu, 1H), 3.36 (ad, y - 6.2 Hz, ZH), 2.95 (aa, Y - 10.6, 7.5 Hz, 1H), 2.40 (aa, 9 - 10.6, 7.6 Hz, 1H), 2.03 (peri, U - 7.7 Hu, 1H), 1.86 (t, 1H), 1.68 (aa, U - 12.1, 8.2 Hz, 1H), 1.47 - 1.22 (t, 5H ), 1.01 (yes, U - 12.1, 8.8 Hz, 1H).

Stage 5: tert-butyl-(45)-4-(33-hydroxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate

(c) here

NM M r.s t s r.s on r.s on

To a solution of 3-((35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl)|propane-1-ol (1.85 g, 11.33 mmol) (1.85 g) in methyl-tert -butyl ether (11.5 ml) was added tert-butoxycarbonyl-tert-butyl carbonate (2.60 g, 11.91 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere. After 5 p.m. the reaction mixture was diluted with water and extracted. The aqueous layer was extracted again with methyl tert-butyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a clear oil (2.94 g). The clear oil was purified by flash chromatography (silica, 3095 ethyl acetate in hexane) to give tert-butyl (45)-4-(3-hydroxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.41 g , 81 95) in the form of a transparent oil. 1H NMR (400 MHz, DMSO-46) b 4.36 (I, 9 - 5.2

Hz, TTN), 3.61 - 3.48 (t, 1H), 3.37 (d, U - 6.0 Hz, 2H), 2.76 (d, U - 10.1 Gu, 1H), 2.14 - 1.96 (t, 1H), 1.95 - 1.77 (t, 1H), 1.48 - 1.24 (t, 14H).

Stage 6: tert-butyl-(45)-4-(3-methylsulfonyloxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (c) (c) o- o-

M M ras v.s vs on vs ov //x oo

To a solution of tert-butyl (45)-4-(3-hydroxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.41 g, 9.149 mmol) in methyl tert-butyl ether (15 ml) triethylamine (1.111 g, 1.530 mL, 10.98 mmol) was added followed by methanesulfonyl chloride (781 µL, 10.09 mmol) in an ice water bath over 5 minutes. A white precipitate immediately formed.

The temperature of the reaction mixture was brought to room temperature. Then the reaction mixture was diluted with methyl tert-butyl ether, filtered, washed with water, dried over sodium sulfate, filtered and concentrated. After standing overnight, tert-butyl (45)-4-(3-methylsulfonyloxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.64 g, 81 95) solidified to a white solid. 1H NMR (400 MHz, DMSO-ab) 5 4.19 (i, U - 6.4 Hz, 2H), 3.63 - 3.50 (t, 1H), 3.16 (5, ЗН), 2.79 (d, U - 10.3 Hz, 1H) , 2.17 - 2.02 (t, 1H), 1.97 - 1.80 (t, 1H), 1.73 - 1.58 (t, 2H), 1.47 - 1.26 (t, 12H).

Stage 7: tert-butyl-(45)-4-(3Z-azidopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (c) x o- (c)

Mores ros y r.s still U z ukh r.s M oo

To a solution of tert-butyl (45)-4-(3-methylsulfonyloxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.64 g, 7.576 mmol) in M,M-dimethylformamide (26 ml) at sodium azide (1.07 g, 16.46 mmol) was added at room temperature. The reaction mixture was heated to 50 C and stirred in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (200 ml) and washed with water (50 ml).

The organic layer was dried over sodium sulfate, filtered and concentrated. Heptane was added and concentrated to remove excess M,M-dimethylformamide to give tert-butyl (45)-4-(3-azidopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (1.77 g, 80, 2 95). IN NMR (400

MHz, DMSO-ab) 5 3.55 (a, U - 10.7, 7.1 Gu, 1H), 3.32 (I, 2H), 2.85 - 2.70 (t, 1H), 2.20 - 2.01 (t, 1H), 1.88 (9, U - 14.0, 13.5, 6.1 Hu, 1H), 1.61 - 1.28 (t, 14H).

Stage 8: tert-butyl-(45)-4-(33-aminopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate. (c) o-/ s--o

M

MN r,s M. ro 2

Platinum oxide was added to a solution of tert-butyl (45)-4-(3-azidopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (1.77 g, 6.137 mmol) in ethyl acetate (330.8 ml) (50.68 mg, 0.2232 mmol). The reaction mixture was hydrogenated using a Vispidiazyzieg hydrogenation apparatus.

The mixture was purged three times under vacuum with nitrogen, then three times under vacuum with hydrogen (0.4 L). The reaction mixture was stirred under a hydrogen atmosphere at 930 rpm at a hydrogen pressure of about 2.18 bar at 257 for 18 hours. 337 ml of gaseous hydrogen was consumed. The reaction mixture was filtered through celite and washed with water (25 mL). The organic layer was washed with brine (25 ml), dried with sodium sulfate, filtered and concentrated, obtaining tert-butyl (45)-4-(3-aminopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-i-carboxylate (1, 66 g, quantitative yield) in the form of a dark oil. 1H NMR (400 MHz, DMSO-ab) b 3.53 (ai, U - 12.2, 6.5 Hz, 1H), 2.76 (d, U - 10.2

Hz, 1H), 2.18 - 1.99 (t, 1H), 1.86 (Id, U - 15.8, 14.2, 6.1 Hz, 1H), 1.55 - 1.21 (t, 16H).

Stage 9: tert-butyl-(4S)-4-N3-(b-sulfamoyl-2-pyridyl)amino)propyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate. h o o o o M o zhM/I ra hu o Z nom - i nl vh

M | Vos M Mykh r.s M 2 r.s o» o VO

IS

Diisopropylethylamine (1, 28 mL, 7.349 mmol), followed by b6-fluoropyridine-2-sulfonamide (1.31 g, 7.436 mmol). The reaction mixture was placed under a nitrogen atmosphere and stirred at 85 "C for 18 hours. The reaction mixture was diluted with methyl tert-butyl ether (50 ml) and extracted with water (20 ml). The organic layer was washed with brine, dried over sodium sulfate, filtered and was concentrated. The residue was dissolved in dichloromethane and purified by chromatography on silica gel (60 95 ethyl acetate in hexane). For the combined fractions containing the product, a second purification was completed by chromatography on silica gel (gradient 095 to 595 methanol in dichloromethane) to give tert-butyl (45)-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl/|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (1.72 g, 67 90) in the form of a white sticky solid substances. IN NMR (400 MHz, DMSO-46) b 7.51 (I, 9 - 8.5, 7.2 Hz, 1H), 7.06 (5, 2H), 7.01 - 6.88 (t, 2H), 6.61 (y, U - 8.4 Hz, 1H), 3.55 (d, U - 9.2 Hz, 1H), 3.30 - 3.21 (t, 2H), 2.88 - 2.71 (t, 1H), 2.19 - 2.00 (t, 1H), 2.01 - 1.78 (t, 1H), 1.66 - 1.27 (t, 14H).

Stage 10: tert-butyl (45)-4-13-C(6-C2-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine- 3-carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate

Vos M. so, so,

To a solution of 2-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (250 mg, 0.6892 mmol) in tetrahydrofuran ( 2.058 ml) was added carbonyldiimidazole (134 mg, 0.8264 mmol). The reaction mixture was stirred at room temperature for 30 min.

Carbonyldiimidazole (11.8 mg, 0.07277 mmol) was added and allowed to stir for another 30 min. a solution of tert-butyl (45)-4-IZ3-(6b-sulfamoyl-2-pyridyl)amino|propyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (307 mg, 0.7334 mmol) in tetrahydrofuran (420 μL) dropwise, followed by 1,8-diazabicyclo/5.4.FO1undec-7-ene (310 μL, 2.073 mmol). The reaction was continued to stir at room temperature under a nitrogen atmosphere. After 18 h, water (8.2 ml), ethyl acetate (25 ml) and hydrochloric acid (710 μl 6 M, 4.260 mmol) were added, obtaining pH - C in the aqueous layer. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification was carried out using flash chromatography (50 95 ethyl acetate in hexane) to obtain tert-butyl (45)-4-(3-I((6-Ce-chloro-6-I3-(2-dispiro(2.0.2.1 |heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (308 mg, 59 95). MO-IER t/2 calculated 759.35, found 760.4 (M'-1)k, retention time: 2.20 min (Method RH C).

Stage 11: M-((6-IZ-K35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I3-(2-dispiro |2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide

YO POM dsch- NM d- NM and shchei and TRA and so, SO," so, SO,"

To the solution tert-butyl (45)-4-I3-C(6-C2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3 -carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (308 mg, 0.3565 mmol) in dichloromethane (1.26 mL) and toluene (624 μL) was added trifluoroacetic acid (411 μl, 5.335 mmol), and the mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was concentrated, diluted with toluene (4.989 ml) and concentrated at 45°C to obtain /-M-I((6-I3-((35)-5,5-

Zo bis(trideuteromethyl)pyrrolidin-3-yl|propylamino|-2-pyridyl|sulfonyl|-2-chloro-6-|3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl Ipyridine-Z-carboxamide (trifluoroacetate salt) (276 mg, 100 90). MO-IER tp/2 calc. 659.2928, found 660.4 (M'-1)k; retention time: 1.11 min. (Method of RH C).

Stage 12: (145)-8-I3-(2-idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-di(trideutero)methyl-2Ab6 -thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione ( compound 274)

(0)

M o o o z M z Y ie SOS

Mo - M ikh | N w-- NM - w 5-0 M M Y w- all MN

TRA so nm so so, I

To the solution M-((6-I3-(35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-2-chloro-6-I3-(2-dispiro |2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) (356 mg, 0.4598 mmol) in MMP (8.6 ml) was added potassium carbonate (322 mg , 2.330 mmol).

The mixture was carefully acidified with hydrochloric acid (5 mL of 1 M, 5,000 mmol) to give a foamy suspension. The solid was collected by filtration using a medium size frit. The filtrate contained no product and was discarded. The wet precipitate on the filter was dissolved in ethyl acetate (21 ml) and washed with 10 ml of saline. The aqueous phase was separated, and the organic phase was dried over magnesium sulfate, filtered and concentrated by mass to give a light yellow oil. The crude product was diluted with acetonitrile (chromatographed on a C18 column with a reversed phase of 30 g, eluting with a gradient from 60 95 to 100 95 acetonitrile in water, obtaining (145)-8-I3-(2-Idyspiro|2.0.2.1|heptane-7- ylylethoxy)-1H-pyrazol-1-ylI-12,12-di(trideutero)methyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclol 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 274) (135 mg, 47 95) as a cream-colored foam. NN NMR (400 MHz, DMOO-ab) b 12.50 (5, 1H), 8.20 (a, 9 - 2.8 Hz, 1Hn), 7.81 (a, 9U - 8.2 Gu, 1), 7.57 (1, 9 - 7.68 Hz . . ), 1.97 - 1.68 (t,

AN), 1.68 - 1.42 (t, 4H), 1.42 - 1.11 (t, 1H), 0.95 - 0.72 (t, 4H), 0.72 - 0.56 (t, 2H), 0.56 - 0.33 (t, 2H). MO-IER t/ calc. 623.32, found 624.3 (M--1) k; retention time: 1.98 min. (Method РХ 0).

Example 94: Preparation of 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10Abthia-1,3,9, 13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22)12-pentane-8,10,10-trione (racemic atropoisomer 1 ) (Compound 280), 12,20 ,20-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10Abthia-1,3,9,13,14- pentaazatetracyclo| 16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (compound 281) and 20,20,22-trimethyl-4-I3-( 3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10Abthia-1,3,9,13,14-pentaazatetracycloY16,2.1.111,14.02,7|docosa-2 ,4,6,11(22),12-pentane-8,10,10-trione

Zo (racemic atropoisomer 2) (Compound 282)

Di; "-6-08.0О0Й5т- З" se M si 2:1 tikhioge oi ipzeeraganie hedioizotege

Ge) 5 o'clock 5 o uv re; all attention; in cha Z I - 5-2 sa M in 2:1 tikhishge oi ipzeragavie hedioizotege o 52 o 54 / M s 5-4 Shchi 7 M i - Si si in all U moh all y M myh all y myh

Stage 1: tert-butyl-2,2-dimethyl-4-I3-(5-methyl-4-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate and tert-butyl-2,2-dimethyl-4- I3-(3-methyl-4-sulfamoyl-pyrazol-1-yl)upropyl|Ipyrrolidine-1-carboxylate (mixture of inseparable regioisomers 2:1) o M M

KU ХМ ня и 7 и ); nd m "m M m u / sh ----- nya

Mn

OM5 MVos

Vos M 2:1 tihiige oi ipzeragavie hedioizogpege

M,M-dimethylformamide (20 mL), carbonate potassium (2.44 g, 17.65 mmol) and 5-methyl-1H-pyrazole-4-sulfonamide (947 mg, 5.875 mmol). The reaction was heated at 65 "C for 24 h. The reaction mixture was filtered, and the flask and the precipitate on the filter were additionally washed with ethyl acetate. The filtrate was evaporated and purified by HPLC (20-80 95 acetonitrile in an aqueous gradient with 0.1 95 hydrochloric acid modifier). The purified fractions were evaporated together to give a white foam. -butyl-2,2-dimethyl 4-(3-(3-methyl-4-sulfamoylpyrazol-1-yl)propyl|Ipyrrolidine-1-carboxylate (total yield 972 mg, 41 95), MO-

IER t/2 distr. 400.21442, found 345.2 (Ma-1)4; Retention time: 1.51 min (Method RH B).

The presence in the mixture of products in the ratio of 2:1 was confirmed by 1H NMR analysis.

Stage 2: tert-butyl-4-(3-I(4-(e-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridin-3 -carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl-4-(3-I(4-(2-chloro-6-(3- (3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-33-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (2:1 mixture of inseparable regioisomers)

M M o shcha Mh - t pom WE buried you and he; - ol Z 7-- - 5-4 M SI

MVos sh-

Vos M 2:1 tihishge oi ipzeeragabie hedioizotetg5 (c) (c)

M M all | 5 with De, all | eh z ra; / ovo Is / in Moi M t 5-43 Moi y

M

Vos

VosMm 21 tihiige oi ipzeragavie hedioiizoteg5

2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridin-3-carboxylic acid (952 mg, 2.565 mmol), carbonyldiimidazole ( 469 mg, 2.892 mmol) and tetrahydrofuran (10 ml).

The reaction was heated at 35 "C and stirred for 2 hours. A 2:1 mixture of tert-butyl-2,2-dimethyl-4-(3-(5-methyl-4-sulfamoylpyrazol-1-yl)propyl|pyrrolidin-1 -carboxylate and tert-butyl-2,2 dimethyl-4-I3-(3-methyl-4-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (965 mg, 2.409 mmol) and 1,8-diazabicyclo| 5.4.Oundec-7-ene (1.10 mL, 7.356 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified directly by silica gel chromatography using a gradient of 20 95 to 100 95 ethyl acetate in hexane. regioisomeric products, tert-butyl 4-I3-(4-((2-chloro-6-

IZ-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-5-methylpyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1 -carboxylate and tert-butyl 4-(3-I(4-(2g-chloro-6-|3- (3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridin-3- carbonyl|sulfamoyl|-3-methylpyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (total yield 1.073 g, 60 9) was isolated as a white foam. MOS-IER t/2 cal. 745, 2636, found 746.4 (Ma1)k Retention time: 1.85 min (Phase 0 method) The regiochemical ratio of the mixture (2:1) was confirmed by 1H NMR.

Stage 3: 2-chloro-M-I(1-3-(5,5-dimethylpyrrolidin-3-yl)/propyl|-5-methylpyrazol-4-yl|sulfonyl-6-I3-(3,3,3 -trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-Z-carboxamide and 2-chloro-M-(1-I(3-(5,5-dimethylpyrrolidin-3-yl)propyl|-Z- methylpyrazol-4-yl|Isulfonyl-6-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (2:11 mixture of inseparable regioisomers)

OM OM s y t ih k.s y she s | N Lee; - | n ra; - M. - M M - M 6- M SI , 6-0 M SI - Y Y/"- --

Vos

Vos M 21 tihishge oi ipzeeragarie hedioizotegv

OM HOUSE g zr so -y

I- M 2 ko - M FI km -0. M Gei), 5-0 M SI

And nm 21 tihiige oi ipzeragarie hedioizoteg5

In a round-bottomed flask containing a 2:1 mixture of tert-butyl 4-(3-14-(2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl |Ipyridine-3-carbonyl|Isulfamoyl|-5-methylpyrazol-1-yl|Ipropyl|/- 2,2-dimethylpyrrolidine-i-carboxylate and tert-butyl 4-(3-I(4-(2-chloro-6 -(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-3-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine -1-carboxylate (1.068 g, 1.431 mmol) was added dichloromethane (15 mL) and trifluoroacetic acid (4.4 mL, 57.11 mmol). The reaction mixture was allowed to stir for 1 h at room temperature. The reaction was evaporated to dryness.

Saturated sodium bicarbonate and brine were added, and the reaction mixture was extracted with ethyl acetate. The organic layer was evaporated to give the product, but a significant amount of product still remained in the aqueous layer after two more extractions with ethyl acetate. Therefore, the aqueous layer was evaporated to dryness, dry acetone was added to the solid and filtered.

The dissolved acetone was evaporated and combined with the organic layers to obtain 2-chloro-M-|1-

13-(5,5-dimethylpyrrolidin-3-yl)propyl|-5-methylpyrazol-4-yl| sulfonyl-6-I(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxamide and 2-chloro-M-HP1-(3-(5,5 -dimethylpyrrolidin-3-yl)upropyl|-3-methylpyrazol-4-yl|sulfonyl-6-I(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridin-3 -carboxamide (2:1 mixture of inseparable regioisomers) (920 mg, 100 95). MO-IER t/2 calcd. 645.2112, found 646.3 (M--1) k; retention time: 1.45 min. (Method of RH B).

Stage 4: 0 20,20,22-trimethyl-4-13-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3, 9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (racemic atropoisomer 1) (compound 280), 12,20,20-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3,9,13 ,14- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (compound 281) and 20,20,22-trimethyl- 4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6bthia-1,3,9,13,14-pentaazatetracyclo|16.2.1.111,14, 02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (racemic atropoisomer 2) (Compound 282)

ISH I IM es uva re, all uva ra; u ra 7 a 5-7 21 tikhioge oi ipzeragabie hedioizotege gasetis aigorizoteg 1 gasetis aigorivoteg 2

Cesium fluoride (432 mg, 2.844 mmol), potassium carbonate (984 mg, 7.120 mmol), molecular sieves Z A and a solution of a mixture of regioisomers, 2-chloro-M-|(1-(3- ( 5,5-dimethylpyrrolidin-33-yl)propyl-5-methylpyrazol-4-yl sulfonyl-6-13-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl Ipyridine-3-carboxamide and 2-chloro-M-(1-(3-(5,5-dimethylpyrrolidin-3-yl)upropyl|-3-methylpyrazol-4-yl| sulfonyl-6-I(3-(3 ,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxamide (2:1 mixture of inseparable regioisomers) (920 mg, 1.424 mmol) in dimethyl sulfoxide (55 mL). The reaction mixture was purged with nitrogen and heated at 150 overnight. The reaction mixture was cooled to room temperature, filtered, washed with brine, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and purified by HPLC (10 95 -70 to acetonitrile in water with 0.1 96 modifier with hydrochloric acid) with obtaining as the first eluted atropoisomer /regioisomer 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3,9 ,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (racemic atropoisomer 1) (compound 280) (45 mg, 10 95). "IN NMR (400

MgHu, DMSO-ab) b 12.41 (5, 1H), 8.19 (j, U - 2.8 Hu, 1H), 7.86 (5, 1H), 7.77 (a, U - 8.2 Hz, 1H), 6.93 (a, - 8.2 Hz, 1H), 6.16 (a, U - 2.68 Hu, 1H), 4.38 (y, U - 14.2 Hu, 1H), 4.23 (5, 2H), 4.01 (i, U - 13.7 Hz, 1H), 2.05 (5, ЗН), 1.89 - 1.70 (t, ЗН), 1.55 (5, ЗН), 1.48 (5, ЗН), 1.44 - 1.28 (t, 2Н), 1.23 (5, 6Н), 1.08 (а, У 2 11.1 Gu, 1H). MO-IER t/2 calc. 609.2345, found 610.4 (M 1); Retention time: 3.01 min (method РХ 0). The second eluted atropoisomer/regioisomer was 12,20,20-trimethyl-4-I(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10.Ab-thia -1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 281) ( 73 mg, 17,965). MSO-IER t/2 calcd. 609.2345, found 610.4 (M--1)k; retention time: 3.07 min. (Method РХ 0). Third eluted atropoisomer/regioisomer was 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10AX6-thia-1,3,9,13 ,14- pentaazatetracyclo/16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (racemic atropoisomer 2) (Compound 282) (19 mg , 4 95). MO-IER t/72 calculated 609.2345, found 610.4 (MA) k, retention time: 3.14 min (Method РХ 0).

Example 95: Preparation of (145)-8-(3-(2-hydroxy-3-(/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab6-thia -3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10),6,8,19(23),20-hexane-2, 2,4-trione (diastereomer 1) (Compound 284) and (145)-8-(3-2-hydroxy-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12 ,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10),6,8,19(23 ),20-hexane-2,2,4-trione (diastereomer 2) (Compound 283)

oh i ah

M - M and 00 - --she 3/7 shsh- MN

IS

POM YO

M. - Mykh ' M. - M y z/- shsh- MN Z sh- MN

E E

Faziegeoteg 1 aiazieegeoteg 2

Stage 1: (145)-8-(3-(2-hydroxy-3-|1-"trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6-thia- 3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5(10),6,8,19(23),20-hexane-2,2, 4-trione (diastereomer 1) (Compound 284) and (145)-8-(3-(2-hydroxy-3-11-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-12, 12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5(10),6,8,19(23), 20-hexane-2,2,4-trione (diastereomer 2) (Compound 283) o Kui 3/7 shsh- MH

Oh oh oh oh oh

M MY do o m 4 M M y - tso o Dan M M M y

Z/7 -k mn Z -. MN

E E

Phasiegeoteg 1 aiazeegeoteg 2 (145)-8-(3-2-hydroxy-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6b-thia-3, 9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (3.24 g, 8.383 mmol) was subjected to chiral separation by means of NCR chromatography using a SpigaIRak Is column (250 X 10 mm, particle size 5 μm) with a mobile phase of 44 95 acetonitrile/methanol (90:10)/56 95 dioxide carbon at 10 ml/min for 12.0 min (injection volume - 70 μl of a solution of 22 mg/ml in acetonitrile/methanol (90:10)3) with obtaining (145)-8-(3) as the first eluted diastereomer -2-hydroxy-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18,23-pentaazatetracycloi|17.3. 1.111,14.05,10|hetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (diastereomer 1) (compound 284) (6.8 mg, 49 95) in the form of a white solid; 1H NMR (400 MHz, DMSO-ab) b 12.52 (5, 1H), 8.22 (y, Y - 2.8 Hz, 1H), 7.82 (0.9 -8.2 Hz, 1H), 7.57 (I, Y - 7.9 Hz , 1H), 7.05 (y, U - 7.2 Hz, 1H), 6.98 (5, 1H), 6.92 (9.9 2 8.2 Hz, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.13 ( , U - 2.8 Gu, 1H), 5.07 (a, U - 5.7 Hz, 1), 4.10 (a4,9 5.2

Gu, 2H), 4.00 - 3.72 (t, 2H), 3.16 (5, 1H), 2.95 (y, U 2 13.5 Hz, 1H), 2.71 (5, 1H), 2.35 (a, U - 17.2 Hz, 1H ), 2.18 - 2.07 (t, 1H), 1.98 (aa, U - 14.9, 4.0 Hz, 1H), 1.86 (da, 9 - 11.5, 5.2 Gu, 1H), 1.76 (5, 1H), 1.68 (5, 1H), 1.67 - 1.60 (t, ЗН), 1.57 (а, У - 12.6 Hz, 2Н), 1.52 (5, ЗН), 1.33 (Y, У - 12.0 Г, 1Н), 1.05 - 0.90 (t, 2Н ), 0.90 - 0.70 (t, 2Н); MO-IER t/2 calc. 663.24506, found 664.4 (M-a-1) t; Holding time: 1.9 min. (Method of RH E). and as the second eluted diastereomer (145)-8-(3-(2-hydroxy-3-11-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab6- thia-

3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5(10),6,68,19 (23),20-hexane-2,2 ,4-trione (diastereomer 2) (compound 283) (7.62 mg, 54 95) as a white solid; 1N

NMR (400 MHz, dimethylsulfoxide-4y6b) b 12.52 (5, 1H), 8.22 (y, U - 2.68 Hz, 1H), 7.82 (a,9 - 8.2

Gu, 1TN), 7.58, 9 - 7.9 Gu, 1H), 7.06 (a, U - 7.2 Hz, 1H), 7.04 - 6.94 (t, 1H), 6.92 (a, U - 8.2 Hz, 1H), 6.71( a,9 8.5 Hz, 1H), 6.14 (y, 9 - 2.7 Hz, 1H), 4.14 - 4.06 (t, 2H), 3.96 (ar, U - 15.9, 6.0, 5.0 Gu, 2H), 3.16 (5, 1H), 2.95 (a, U - 13.3 Hz, 1H), 2.70 (a, 9U 2 11.1 Hu, 1H), 2.50 - 2.36 (t, 1H), 2.13 (5, 1H), 1.98 (aa, U - 15.0 , 4.0 Hz, 1H), 1.86 (aa, 9 - 11.6, 5.2 Hz, 1H), 1.77 (5, 1H), 1.71 - 1.65 (t, 1H), 1.63 (5, 1H), 1.61 (5, ЗН) . ); MO-IER t/2 calc. 663.24506, found 664.4 (Ma1)k; Retention time: 1.9 min (method РХ E).

Example 96: Preparation of (145)-12,12-dimethyl-8-(3-13-1/1-(trifluoromethyl)cyclopropyl)|-2,2,3,3-tetradeutero-propoxy)-1H-pyrazole- 1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20 -hexane-2,2,4-trione (Compound 287) ro ro ro es ono ber es OH 5ier? Es OoMm5 ver z z -- - |fЯ«-k "z r Z Azh ro o vo o

Bud M ro nioo8 ro M AH ra p, vivr 4 KK vir 5 o, y - (c) verb

Sh-633 on on - ro I b c) c)

В ЖЖ В М МН ра в; I saw 7 |c; as - 7 o'clock 8

I DY yun vs o ve o si M si (9) (9) swa ach M nm skh

R 5-47 Me vve o rvana M r v, 9); I paid 10 ka for -sh- o KU o m o Ku

Stage 1: 1,1,2,2-tetradeutero-2-|11-(trifluoromethyl)cyclopropyl|ethanol ro ro ro ro

To a suspension of lithium aluminum deuteride (1.0872 g, 27.204 mmol) in anhydrous tetrahydrofuran (50 mL) was added a solution of 2,2-dideutero-2-(1-(trifluoromethyl)cyclopropyl|acetic acid (4 g, 20.926 mmol) in anhydrous tetrahydrofuran (50 ml) dropwise at 0 "C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with diethyl ether (50 ml) and cooled to 0 "C, and then quenched successively with water (1.1 ml ), 15 95 with sodium hydroxide (aqueous, 1.1 ml) and water (3.3 ml).

The reaction mixture was stirred at room temperature for 30 minutes, and then it was filtered through a pad of celite and dried over anhydrous magnesium sulfate. Filtered and

The filtrate was concentrated under reduced pressure to give 1,1,2,2-tetradeutero-2-(1-(trifluoromethyl)cyclopropyl|ethanol (3.288 g, 92 965) as a clear liquid. 1H NMR (250

MGu, SOSIZ) b 1.42 (5, 1H), 1.03 - 0.89 (t, 2H), 0.67 (t, 2H).

Stage 2: (1,1,2,2-tetradeutero-2-P1-("trifluoromethyl)cyclopropyl|ethyl|methanesulfonate ro ro ek ek ---" ro ro

To a solution of 1,1,2,2-tetradeutero-2-/1-(trifluoromethyl)cyclopropyl|stanol (3.288 g, 19.334 mmol) and triethylamine (5.8692 g, 8.0843 mL, 58.002 mmol) in dichloromethane (35 ml). methanesulfonyl chloride (2.6577 g, 1.7957 mL, 23.201 mmol) was added dropwise at 0 "C. The reaction mixture was stirred at room temperature for 1 h, and then diluted with dichloromethane (50 mL) and 10 95 citric acid (50 mL) . The two layers were separated and the organic layer was washed with saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0 95 to 70 95 of diethyl ether in hexane to give I1,1,2,2-tetradeutero-2-(1-(trifluoromethyl)cyclopropyl|IIethyl|methanesulfonate (3.982 g, 83 95) as a clear liquid. 1H

NMR (250 MHz, SOSIZ) b 3.01 (5, ЗН), 1.03 (t, 2Н), 0.71 (t, 2Н).

Stage 3: 2,2,3,3-tetradeutero-3-|11-(trifluoromethyl)cyclopropyl|Ipropanenitrile ro; ro,

ES OM - zhEb 07 ro ro,

Sodium cyanide (980.93 mg, 20.016 mmol). The reaction mixture was stirred at 70 "C for 2 days. After cooling to room temperature, the reaction mixture was poured into water (50 ml). The aqueous solution was extracted with diethyl ether (3 x 50 ml). The combined organic layers were washed with water ( 2 x 50 ml) and saline solution (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain 2,2,3,3-tetradeutero-3-|1-(trifluoromethyl)cyclopropyl|propanenitrile (2.769 g , 96 95) in the form of a light yellow oil.YAN NMR (250 MHz, SOSIS) 6 1.12 - 1.00 (t, 2H), 0.78 - 0.66 (t, 2H).

Stage 4: 2,2,3,3-tetradeutero-3-|/1-(trifluoromethyl)cyclopropyl|Ipropanoic acid. vd EM ro ei|o

Es 0 on ro ro

Sodium deuteroxide (6.3166 g, 40 95 wt./wt) was added to a solution of 2,2,3,3-tetradeutero-3-(11-(trifluoromethyl)cyclopropyl|ipropanenitrile (2.769 g, 15.405 mmol) in CH3Smzhaget (30 ml). wt. 61.620 mmol) and deuterium oxide (6 ml). The reaction mixture was stirred at 70 "С for 16 h. The reaction mixture was cooled to room temperature and concentrated under vacuum.

The aqueous solution was diluted with water (50 ml) and washed with diethyl ether (2 x 50 ml). Then the aqueous phase was acidified to pH 1 and extracted with diethyl ether (3 x 50 ml). These combined ether layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2,2,3,3-tetradeutero-3-(|1-(trifluoromethyl)cyclopropyl|propanoic acid (2.737 g, 91 95) as a yellow liquid. 1N

NMR (250 MHz, SOSIZ) b 1.08 - 0.83 (t, 2H), 0.72 - 0.49 (t, 2H).

Stage 5: 2,2,3,3-tetradeutero-3-|/1-(trifluoromethyl)cyclopropyl|Ipropan-1-ol ro,o b sho:

CC ---I 5 3 CC

A solution of 2,2,3,3-tetradeutero-3-|1-(trifluoromethyl)cyclopropyl|Ipropanoic acid ( 2.737 g, 13.967 mmol) in anhydrous tetrahydrofuran (20 ml) dropwise at 0 "C. The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with diethyl ether (20 ml) and cooled to 0 "C. Water (0.7 ml), 15 95 sodium hydroxide (aq.) (0.7 ml) and water (2.1 ml) were added sequentially.

The reaction mixture was stirred at room temperature for 30 min and filtered through a layer of celite. The filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to obtain 2,2,3,3-tetradeutero-3-(/1-(trifluoromethyl)cyclopropyl|Ipropan-1-ol (2.04 g, 84 95) in the form of a pure liquid. 1H NMR (250 MHz, DMSO-46) b 4.44 (I, 9) - 5.1 Hu, 1H), 3.38 (5, 2H), 0.95 - 0.79 (t, 2H), 0.68 (ai, U - 2.2, 1.2 Hz, 2H).

Stage 6: tert-butyl 3-(2,2,3,3-tetradeutero-3-|1- (trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate (c) (c) ra

Mromo XX ra NI ts vi 9 th scha on no ro --

Es ts r

To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2.08 g, 11.29 mmol) and 2,2,3,3- tetradeutero-3-(/1-(trifluoromethyl)cyclopropyl|Ipropane -i-ol (2.04 g, 1185 mmol) in tetrahydrofuran (26 mL) was added triphenylphosphine (3.108 g, 11.85 mmol).Diisopropylazodicarboxylate (2.396 g, 11.85 mmol) was slowly added dropwise over 10 min to the mixture. (exothermic effect noted). The reaction mixture was stirred at room temperature for 2 h. The tetrahydrofuran was removed by ip massio. To the crude reaction mixture was added toluene (16.64 mL) and the mixture was stirred overnight. The solution was concentrated by ip massio.

The crude product was purified by silica gel chromatography using a shallow gradient of 10095 hexanes to 10095 ethyl acetate to afford tert-butyl-3-(2,2,3,3-tetradeutero-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1 -carboxylate (2.43 g, 64 95) in the form of a clear syrup. MSOS-IER t/2 calcd. 338.17554, found 339.0 (Ma1)-; Retention time: 0.75 min. (Method RH A) .

Stage 7: 3-(2,2,3,3-tetradeutero-3-(1-(trifluoromethyl)cyclopropyl|propoxy|-1H-pyrazolo) M

AJ I nn r s and r

Tert-butyl-3-(2,2,3,3-tetradeutero-3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1-carboxylate (2.43 g, 7.182 mmol) was dissolved in dichloromethane (24.3 mL) with trifluoroacetic acid (8.297 mL, 107.7 mmol), and the reaction mixture was stirred at room temperature for 120 minutes. The reaction mixture was evaporated and the resulting oil partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted twice more with ethyl acetate, then the organic layers were combined, washed with saline, dried over sodium sulfate, filtered and evaporated, obtaining in the form of an oil 3-(2,2,3,3-

Zo tetradeutero-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy|-1H-pyrazole (1.711 g, 100 95). MO-IER t/72 calc. 238.12311, found 239.1 (M--1) k; retention time: 0.54 min. (Method of RH A).

Stage 8: tert-butyl 2-chloro-6-I3-(2,2,3,3-tetradeutero-3-|(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate ( c) r edge - in | 5 (c) --- another 5-47 MU p

ES c) si Mi SI kva dO

With r shko; c c)

2,6-Dichloropyridine-3-carboxylic acid tert-butyl ester (1.782 g, 7.182 mmol), 3-(2,2,3,3-tetradeutero-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy|-1H- pyrazole (1.711 g, 7.182 mmol) and potassium carbonate (1.192 g, 8.625 mmol) were combined in anhydrous dimethyl sulfoxide (34.22 mL). 1,4-diazabicyclo(2.2.2|octane (161.3 mg, 1.438 mmol) and the mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (65.81 mL) and stirred for 15 min. The resulting white solid was filtered and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate The mixture was filtered and the filtrate was evaporated, obtaining tert-butyl 2-chloro-6-I(3-(2,2,3,3-tetradeutero-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl| Pyridine 3-carboxylate (2.58 g, 80 95) as a white solid, MO-IER t/2 calcd 449.16312, found 450.0 (MA) k, retention time: 0.91 min ( Method of РХ A).

Stage 9: 2-Chloro-6-I3-(2,2-dideutero-2-dispiro(|2.0.2.1|heptan-7-yl-ethoxy)pyrazol-1-yl|pyridin-3-carboxylic acid

Mu - all vva

Tert--butyl-2-chloro-6-I3-(2,2,3,3-tetradeutero-3-|11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylate (2, 58 g, 5.735 mmol) was dissolved in dichloromethane (25.8 mL) with trifluoroacetic acid (6.627 mL, 86.02 mmol) and the reaction mixture was stirred at room temperature for 16 h. Trifluoroacetic acid (2.209 mL, 28.67 mmol) was added ) and stirring was continued for 30 minutes. The reaction mixture was evaporated and ether was added to the resulting solid, and then the ether was removed under reduced pressure. This was repeated twice more to give a white solid, which was recrystallized from dichloromethane to give the pure product as a solid ( collection 1).The product remained in the filtrate, which was evaporated to give an off-white solid, which was dissolved in ethyl acetate and washed with 5N sodium hydroxide (2x), then 1N hydrochloric acid(s), then dried (sodium sulfate) , filtered and concentrated to a white solid, which was purified by chromatography on silica gel using a shallow gradient from 10095 dichloromethane to 2095 methanol in dichloromethane, which resulted in poor resolution. Fractions containing the product were combined, concentrated, filtered, and purified using a reversed-phase HPLC-MS method using an Ipa C18 (2) column (75 x 30 mm, 5 μm particle size) sold by Rpepotepeh ( art.: 00С-4252-00-АХ), and running with a double gradient from 20 95 to 80 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "С) to obtain the pure product, which was combined with the initially crystallized solid material to obtain 2-chloro-6-I3-(2 ,2,3,3-tetradeutero-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (1.75 g, 78 95) in the form of a white solid. MO- IR t/2 calcd 393.10052, found 394.0 (M--1)- Retention time: 0.72 min (RC Method A).

Stage 10: tert-butyl (45)-4-I3-C(6-Ce-chloro-6-I3-(2,2,3,3-tetradeutero-3-|1- (trifluoromethyl)cyclopropyl|propoxy|pyrazole -1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridylyamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate) (c) M n M

M y- x - zh mm Ks s M 2 m oIe or bob AH

To a solution of 2-chloro-6-I3-(2,2,3,3-tetradeutero-3-|1- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (1 g, 2.539 mmol) in tetrahydrofuran (6.832 mL), carbonyldiimidazole (514.7 mg, 3.174 mmol) (recrystallized from tetrahydrofuran) was added and the mixture was stirred at room temperature for 3 h, then tert-butyl (45)-2,2-dimethyl- 4-I3-(b-sulfamoyl-2-pyridyl)amino|Ipropyl|Ipyrrolidine-i-carboxylate (1.047 g, 2.538 mmol) as a solution in tetrahydrofuran (2.5 mL) and then 1,8-diazabicyclo/5.4 .FOundec-7-ene (1.192 mL, 7.971 mmol), and the resulting mixture was stirred for b hours at room temperature. The reaction mixture was diluted with water and ethyl acetate, then hydrochloric acid (1.418 mL, 12 M, 17.02 mmol) was added, pH of the aqueous layer was 1. The layers were separated and the organic layer was washed with water (15) and brine (1X) then dried over sodium sulfate, filtered and concentrated to a white foam which was purified on a reverse phase column 275 g of C18, eluting with a gradient from 50 95 to 10095 acetonitrile in water to obtain tert-butyl (45)-4-(3-((6-Ce-chloro-6-I3-(2,2,3,3- tetradeutero -3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|isulfamoyl|-2-pyridyliamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (1.261 cРХs, 63 95) as a white solid. MO-IER t/: calc. 787.3044, found 788.2 (Ma) k; retention time: 0.89 min. (Method of RH A).

Stage 11: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridylI|sulfonyl|- 6-I3-(2,2,3, 3-tetradeutero-3-|1-trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridin-3-carboxamide (trifluoroacetate salt)

M -- M yu 5 DAI vv te

Tert-butyl (45)-4-III3-C(6-Ce-chloro-6-I3-(2,2,3,3-tetradeutero-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1 -yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (1.409 g, 1.787 mmol) was dissolved in dichloromethane (6.147 mL) and trifluoroacetic acid (5.509 mL) was added to the mixture , 71.51 mmol), and the mixture was stirred at room temperature for 90 minutes. The mixture was concentrated to dryness under reduced pressure, 50 ml of toluene was added and removed by rotary evaporation (water bath 45 "С). 50 ml of toluene was again added and removed by a rotary evaporator ( water bath 45 "C), then dried in oil to obtain 2-chloro-M-I((6-(3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2-pyridyl|sulfonyl) -6-(3-(2,2,3,3-tetradeutero-3-|1- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt)) (1.434 g, 100 95 ) in the form of a white solid. MO-IER t/: calc. 687.25195, found 688.2 (Mt) zh; retention time: 0.62 min. (Method RH A).

Stage 12: (145)-12,12-dimethyl-8-(3-13-P1-(trifluoromethyl)cyclopropyl|)|-2,2,3,3-tetradeutero-propoxy)-1H-pyrazole-1- yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 287) o

M OM o 5-4 Me -ya bo dm se Iv ya ad tia NYA

Es r r A E c r

To a solution of 2-chloro-M-((6-(3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2- pyridyl|sulfonyl|-6-(3-(2,2,3 ,3-tetradeutero-3-|1-

To (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (1.434 g, 1.788 mmol) in MMP (86.04 mL) was added potassium carbonate (1.73 g, 12.52 mmol). The mixture was purged with nitrogen for 5 min. The mixture was then heated at 155 °C for 18 h. The reaction mixture was cooled to room temperature and added to water (-200 mL) to give an off-white solid. The mixture was carefully acidified with hydrochloric acid (2.235 mL of 12 M, 26.82 mmol) , to give a foamy suspension. The solid was collected by filtration and washed with water. The filtrate was discarded. The wet filter cake was dissolved in ethyl acetate and dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil which was chromatographed on a C18 reverse phase column 275 g, eluting with a gradient from 50 95 to 100 95 acetonitrile in water to obtain (145)-12,12-dimethyl-8-(3-13-P1-(trifluoromethyl)cyclopropyl)|-2,2,3,3- tetradeuteropropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9 ,19(23),20-hexane-2,2,4-trione (compound 287) (845.2 mg, 73 95) as a white solid. 1H NMR (400 MHz, dmMeoo-ab) b 12.50 (5 , 1H), 8.21 (y, U - 2. 68 Hz, 1H), 7.81 (y, 9 - 8.2 Hz, 1H), 7.58 (aa, U - 8.5, 7.2 Hz, 1H), 7.05 (a, U - 7.1 Gu, 1H), 6.99 (5, 1H) . Hz, 1H), 3.15 (5, 1H), 2.95 (a, U - 13.5 Hz, 1H), 2.71 (5, 1H), 2.12 (5, 1H), 1.86 (yes, 9 - 11.9, 5.3 Hz, 1H ), 1.77 (5, 1H), 1.60 (5, 4H), 1.57 (y, U - 13.9 Hz, 2H),

1.51 (5, ZN), 1.37 - 1.23 (t, 1H), 0.93 - 0.86 (t, 2H), 0.75 (5, 2H). MO-IER t/2 calc. 651.27527, found 652.4 (M.-1) k; retention time: 2.25 min. (Method of RH B).

Example 97: Preparation of 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3, 9,13,14-pentaazatetracyclo/|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (atropoisomer 1, enantiomer 1) (Compound 288) and 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10AX6-thia-1,3, 9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1, enantiomer 2) (Compound 289 ) (6)

Ka vs y: m7 ru y y 5ivr1 gasetis aigorizoteg 1 (6) (6)

M M s y: es ke y: es

N u; and | Н Shshch y, aighorizoteg 1, epapioteg 1 aggorizoteg 1, epapioteg 2

Stage 1: 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9 ,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1, enantiomer 1) (Compound 288) and 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3,9, 13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1, enantiomer 2) (Compound 289) ( 6)

BS | шх м кк шшшщ-/ gasetis aigorizoteg 1 (6) (6)

M M s y es ke y: es

N u; and | N sh u, lu 4 U r 5-4 M U aighorizoteg 1, epapioteg 1 aggorizoteg 1, epapioteg 2

Racemic 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9,13 ,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (45 mg, 0.07381 mmol) (racemic atropoisomer 1 ) was separated by chiral NKR chromatography using SpigaiRak A5-H (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 24 95 acetonitrile:methanol (90:10, 20 mM MNH))/76 95 dioxide carbon at 70 ml/min, obtaining as the first eluted enantiomer 20,20,22-trimethyl-4-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1- il|-10A6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10- trione (atropoisomer 1, enantiomer 1) (Compound 288) (18.6 mg, 83 95). MO-IER t/:2 calcd 609.2345, found 610.4 (Ma1)-4; Retention time: 3, 0 min. (Method LC 0). The second eluted enantiomer was 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|- 10X6-thia-1,3,9,13,14- pentaazatetracycloi|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1, enantiomer 2) (Compound 289 ) (15.5 mg , 69 95). 1H NMR (500 MHz, dmeo-avb) b 12.16 (p5, 1H), 8.19 (a, 9-2.8 Hz, 1H), 7.82 (5, 1H), 7.81 (a, 9-7.9 Hu, 1H), 6.92 (a, 9-7.9 Hz, 1H), 6.10 (j, 9-2.6 Hz, 1H), 4.35 (t, 1H), 4.22 (65, 2H), 4.02 (t, 1H), 2.53 (5, ЗН) , 2.02 (t,

ZN), 1.83 (t, 2H), 1.75 (ai, 9U-12.1 Gu, 5.6 Hz, 1H), 1.54 (5, ZN), 1.47 (5, ZN), 1.36 (d, 9U-15.6 Hz, 12.4

Hz, 2H), 1.22 (5, 6H), 1.12 (t, 1H). MO-IER t/2 calc. 609.2345, found 610.4 (Ma); retention time: 3.0 min. (Method РХ 0).

Example 98: Preparation of (145)-12,12-di(trideutero)methyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 292) about M Ii MM r Z. mo. - I Vosm M. y vivr1 Mom ME with M 2 zier2 ,-74 M a ХА with, МН vs vs t

VosM so, so,

OY PO o uk M si M ih vir Z o dm Ka M M y -Y NM o re MN vs ES

TRA NM so, so,

Stage 1: tert-butyl (45)-4-I3-((6-Ce-chloro-6-(3-(3-(11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3- carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate

MM SI res zy "AKA AL z, mn vs. Iv) and vs. t

Vos M so, so,

To a solution of 2-chloro-6-I3-I3-/1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (175 mg, 0.4490 mmol) in tetrahydrofuran (1.5 ml) was added carbonyldiimidazole (86 mg, 0.5070 mmol), and the mixture was stirred at ambient temperature for 90 min. To this solution was added tert-butyl (45)-4-(3-((6-sulfamoyl-2-pyridyl)amino|propyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (140 mg, 0, 3345 mmol) in tetrahydrofuran (1 mL), followed by 1,8-diazabicyclo[5.4.0)undec-7-ene (135 μL, 0.9027 mmol), and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water ( 5 mL) and the mixture was slowly acidified with hydrochloric acid (1.7 mL 1 M, 1.700 mmol). The mixture was extracted with ethyl acetate (10 mL) and the organic phase was separated. The organic phase was concentrated by mass. The crude product was chromatographed on

to a 0-gram reversed-phase column, eluting with 50-100 95 acetonitrile in water, giving

Zo tert-butyl (45)-4-I3-((6-Ce-chloro-6-I3-I3-P1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|- 2-Pyridylamino|propyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (200 mg, 76905). MO-IER t/2 calcd. 789.31696, found 790.4 (MA); retention time: 3.47 min (Method РХ 0).

Stage 2: M-((6-I3-(35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|Ipropylamino|-2- pyridyl|sulfonyl|-2-chloro-6-I(3-I3 -11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-

Z-carboxamide (trifluoroacetate salt)

her M. Y. M

M | - M and M - M ich 5-5 m si j 5-0 M si d/ re ni du shshch-nm shko; I'm here! tA m so, so, so, so,

That tert-butyl (45)-4-I3-((6-C2-chloro-6-I3-I(3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl| sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (200 mg, 0.2531 mmol) in dichloromethane (3 ml) and toluene (1 ml) was added trifluoroacetic acid (200 μl , 2.596 mmol).

The mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was treated with 10 mL of toluene and concentrated in vacuo to give M-(6-I3-(35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|Ipropylamino|-2-pyridyl sulfonyl| -2-chloro-6-(3-III-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (204 mg, 100 95). MO-IER t/ 72 calcd 689.2645, found 690.3 (M--1) k, retention time: 2.23 min (Method Х 0).

Stage 3: (145)-12,12-di(trideutero)methyl-8-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9 ,11,18,23-pentaazatetracycloi!17.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 292) o o o o o o o

MI Y

M - M ikh M - M ikh d/ w- NM U/ wshch- MN

ЕС щ и вс nm so, so»

To the solution M-((6-I3-(35)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl|Ipropylamino|-2- pyridyl|sulfonyl|-2-chloro-6-I(3-I3- 11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridin-

Potassium carbonate (180 mg, 1.302 mmol) was added to Z-carboxamide (trifluoroacetate salt) (200 mg, 0.2487 mmol) in MMR (6 mL). The mixture was purged with nitrogen for 5 minutes and then heated at 135 C for 22 hours. The reaction mixture was cooled to ambient temperature and diluted with water (10 ml). The mixture was carefully acidified with hydrochloric acid (500 μl 6 M, 3,000 mmol). The suspension was extracted with ethyl acetate (15 ml) and the organic phase was washed with saline. The organic phase was concentrated by mass. The crude product was chromatographed on a 30 g reverse phase column eluting with a gradient of 50 95 to 100 95 acetonitrile in water to give a foam which was dried in a vacuum oven at 45" for 48 hours to give (145)-12,12-di( trideutero)methyl-8-(3-13-(11- (trifluoromethyl)cyclopropyl|ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracycloyl17, 3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 292) (45.2 mg, 27 95) . IN NMR (400 MHz, DMSO-ab) b 12.51 (5, 1H), 8.21 (y, 9 - 2.7 Hz,

Zo 1H), 7.81 (a, 9 - 8.3 Hz, 1), 7.63 - 7.51 (t, 1H), 7.05 (j, 9 - 7.2 Gu, 1H), 6.99 (5, 1H), 6.91 (a, 9 - 8.2 Hz, 1TN), 6.71 (а, 9 - 8.4 Hz, 1Н), 6.12 (90.9. - 2.7 Hz, 1Н), 4.20 (1, 9 - 6.2 Hz, 2Н), 3.92 (5, 1Н), 3.15 (5, 1H), 2.95 (a, U - 13.4 Hz, 1H), 2.75 - 2.65 (t, 1H), 2.10 (a, 9 - 18.4 Gu, 1H), 1.85 (da, 9 - 11.1, 5.2 Gu ) 2H). MO-IER t/2 calc. 653.28784, found 654.4 (M--1)k; Holding time: 2.21 min. (Method of RH B).

Example 99: Preparation of (145)-8-I3-(2-idispiro(2.0.2.1|heptan-7-yl-2-hydroxyethoxy)-1H-pyrazol-1-ylI|-12,12-dimethyl-2A6- thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2, 4-trione (diastereomer 1) (Compound 294) and (145)-8-I3-(2-dispiro|2.0.2.1|heptan-7-yl)-2-hydroxyethoxy)-1H-pyrazol-1-ylI| -12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23) ,20-hexane-2,2,4-trione (diastereomer 2) (Compound 293)

(in)

M x z xx

M | ro Ii u-yb ver 1 no o- Y M M 0955052 i y I o oo o oo r

M | сх M | хх that 5 n | but dm se -I

M (o) no o dyn sl Do hi Mn d- MN aiaztegeoteg 1 diaviegeoteg 2

Stage 1: (145)-8-3-(2-ydispiro(2.0.2.1|heptan-7-yl)-2-hydroxyethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia -3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (di(astereomer 1) (Compound 294) and (145)-8-I3-(2-5 ydispiro(2.0.2.1|)heptan-7-yl-2-hydroxyethoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20 -hexane- 2,2,4-trione (diastereomer 2) (Compound 293) (c)

Ka eh and | eh no o ak WE are not 5 and I iv) I (c)

M uv eh

ХХ 7 хх n | but in M M -e c) but o dm aut rea: m I. - y aiaziegeoteg 2 diaviegeoteg 1 (145)-8-I3-(2-idispiro|2.0.2.1| heptan-7-yl/-2-hydroxyethoxy )-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5 ,7,9,19(23),20-hexane-2,2,4-trione (62 mg, 0.09030 mmol) was subjected to chiral separation by NKR chromatography using SpigaISe! AB-H (column 250 X 10 mm, particle size 5 μm) with a mobile phase of 3895 acetonitrile/methanol (90:10)/62 95 carbon dioxide at 10 ml/min for 28.0 min (injection volume - 70 μl of a solution of 23 mg/ml in acetonitrile/methanol (90:10) with obtaining as the first eluted diastereomer (145)-8-I3-(2-isdispiro|2,0.2.1|)heptan-7-yl.2-hydroxyethoxy )-1H-pyrazol-1-yl|-12,12-dimethyl-2А6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22) ,5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (compound 294) (16.4 mg, 55 95) as a white solid; 1H NMR (400

MgHu, DMOSO-ab) b 12.51 (5, 1H), 8.20 (j, 7 - 2.7 Hu, 1Hn), 7.82 (a, 9 - 8.2 Hz, 1H), 7.58 (I, U - 7.8 Hu, 1H), 7.05 (a, U - 7.2 Hz, 1H), 6.99 (a, U - 9.1 Gu, 1H), 6.91 (a, U - 8.2 Hz, 1H), 6.71 (a, U - 8.5 Hz, 1H), 6.09 ( y, U - 2.7 Hz, 1H), 4.87 (49, U - 5.2, 1.3 Gu, 1H), 4.09 (a, 9 - 5.5 Hz, 2H), 3.92 (a, 9U - 12.6 Hz, 1H), 3.57 ( 4, 9 - 9.2, 5.3 Hu, 1H), 3.16 (a, U - 10.0 Hu, 1H), 2.95 (y, U - 13.3 Hu, 1H), 2.69 (a, U - 9.6

Gu, 1), 2.12 (5, 1H), 1.86 (ai, 9 - 11.9, 5.2 Hz, 1H), 1.76 (5, 1H), 1.60 (5, ЗН), 1.59 - 1.53 (t, ЗН), 1.52 (5, ZN), 1.31 (ad, y - 9.4, 7.1 Hz, 1H), 1.08 (aa, y - 8.9, 5.3, 3.6 Hz, 1H), 0.95 - 0.88 (t, 1H),

0.84 (ada, o - 8.8, 5.2, 3.7 Hz, 1H), 0.73 (ada, 9 - 68.0, 4.8, 3.3 Gu, 1H), 0.63 (aa, 9 - 8.7, 5.2, 3.6 Hz, 2H), 0.60 - 0.54 (t, 2H), 0.52 (y, 9U - 8.4, 3.8 Hz, 1H); MO-IER t/2 calc. 633.2733, found 634.2 (Ma1)4; Retention time: 1.95 min. -1-yl|- 12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9, 19(23),20-hexane-2,2,4-trione (diastereomer 2) (compound 293) (17.3 mg, 60 g) as a white solid; 1H NMR (400 MHz, dimethylsulfoxide-ab) b 12.52 (5, 1H), 8.20 (y, 9 - 2.8 Hu, 1H), 7.82 (a, 9 - 8.2 Hu, 1), 7.58 (1, U - 7.9 Hz , 1H), 7.05 (a, 9 - 7.2 Hz, 1H), 6.99 (a, U - 8.9

Hu, 1H), 6.91 (a, U - 8.2 Hz, 1H), 6.71 (a, 9 - 68.5 Hu, 1H), 6.09 (a, U - 2.7 Hz, 1H), 4.88 (j, U - 5.2 Hz, 1H), 4.15 - 4.05 (t, 2H), 3.92 (0, U - 11.68 Hz, 1H), 3.57 (daa, U - 9.2, 4.8, 1.8 Hz, 1H), 3.16 (a, 9 - 9.6

Hu, 1H), 2.95 (y, U - 13.2 Hz, 1H), 2.70 (5, 1H), 2.12 (5, 1H), 1.85, -6.1 Hu, 1H), 1.76 (5, 1H), 1.61 (5 ) 1H), 0.92 (ai, U - 8.6, 4.2 Hz, 1H), 0.84 (aa, y - 7.4, 5.2, 3.5 Hz, 2H), 0.74 - 0.70 (t, 1H), 0.63 (aa, 9 - 8.9, 5.3, 3.8 Hz, 1H), 0.59 - 0.54 (t, 2H), 0.54 - 0.48 (t, 1H);. MO-IER tp/2 calc. 633.2733, found 634.2 (MAT) k; Retention time: 1.95 min (method RH B).

Example 100: Preparation of (145)-8-(3 /3-hydroxy-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 295) (c) /g he by o, g J o va vier 1 5ivr2 E vers3 R ts vier 4

E (c)

E (c) E xx vo v ko no y o u su schi Mk

ЕЕ о и и Е что Ше Ше ше si We si 0) 0) 9

J

M y-- M y M I

In M si vivrv KU M si II zier9 dk-- --- -- Y NM -it-

EE EE M I o oo

M o oo xx M chn M y I i

M 2 M | n 0 y i 8iver 10 M 4 Mach ohm nn ana / -- Mn (9,

E o-5i77

EE in wai o E E

Stage 1: ethyl-3-oxo-3-|/1-(trifluoromethyl)cyclopropyl|Ipropanoate (en! o o -----

E about E

EE

B b in o

To a suspension of (3Z-ethoxy-3Z-oxopropanoyl)oxypotassium (23.197 g, 136.29 mmol) in acetonitrile (200 mL) was added triethylamine (21.014 g, 28.945 mL, 207.67 mmol) and dichloromagnesium (15.448 g, 162.25 mmol). The mixture was stirred at room temperature for 2 h. A mixture of carbonyldiimidazole (12.628 g, 77.878 mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid (10 g, 64.898 mmol) in acetonitrile (40 mL) was added to the mixture, and the combined mixture was stirred overnight. The mixture was diluted with ethyl acetate (250 mL) and washed with water (500 mL) and brine (500 mL) before drying over sodium sulfate and then filtering. After concentration of the filtrate in vacuum, the organic residue was purified by chromatography on silica gel, eluting with a mixture of 30 95 hexanes-ethyl acetate, to obtain ethyl 3-oxo-3-(/1-(trifluoromethyl)cyclopropyl|propanoate (3.875 g, 25 90). IN NMR (250 MHz, SOSIZ) b 4.17 (da, U - 7.1, 0.6 Gu, 2H), 3.73 (5, 2H), 1.41 - 1.32 (t, ЗН), 1.24 (9, 9 - 7.1, 0.6 Hz, 4H ).

Stage 2: ethyl-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl|propanoate (c) (c) - o ,/t

E E c) ---

E E

E c) E no

To a solution of ethyl 3-oxo-3-/1-(trifluoromethyl)cyclopropyl|propanoate (3.513 g, 15.671 mmol) in EYN (35.130 mL) was added Mavnai (652.16 mg, 0.6901 mL, 17.238 mmol) at -78 "C. The mixture was stirred at 0 "C, and then quenched with 1 M aqueous hydrochloric acid (35 ml).

The organic layer was extracted with ethyl acetate (3 x 100 ml), then washed with brine (100 ml) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give ethyl 3-hydroxy-3-(/1-(trifluoromethyl)cyclopropyl|ipropanoate (3.31 g, 63 95). 1H NMR (250 MHz, SOSIS) b 4.09 (a, 9 - 7.1 Hz, 2H), 3.89 (5, 1H), 2.70 (ad, 9. - 3.1 Gu, 2H), 1.26 - 1.21 (t, ЗН), 0.96 (a, U - 6.9 Hz, 4H).

Stage C: ethyl-3-Egret-butyl (dimethyl)silyl|oxy-3-(1- (trifluoromethyl)cyclopropyl|Ipropanoate (c) , PLt- (c) /t

E (in)

E o - - - - t k

E Y and

E o no M -

To a solution of ethyl 3-hydroxy-3-|1-(trifluoromethyl)cyclopropyl|ipropanoate (3.19 g, 14103 mmol) in dichloromethane (63.800 ml) was added 2,6-lutidine (3.1734 g, 3.4300 ml , 29.616 mmol) and

Igrate-butyldimethyl)silyl Igryfluoromethanesulfonate (5.5918 g, 4.8624 mL, 21.154 mmol) at 0 C. The reaction was stirred at room temperature for 3 h. The solution was diluted with diethyl ether (60 mL) and washed with 1 M hydrochloric acid (60 mL), saturated sodium bicarbonate (60 mL), and brine (60 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl Z-Igret-

Zo butyl(dimethyl)silyl|oxy-3-(1-(trifluoromethyl)cyclopropyl|propanoate (3.51 g, 72 965) in the form of a clear liquid. IN NMR (250 MHz, SOSIS) b 4.12 (d, U - 7.2 Hz, 2H), 3.95 (give, y - 8.5, 3.9, 11

Hu, 1H), 2.71 - 2.59 (t, 2H), 1.33 - 1.19 (t, ЗН), 0.89 - 0.87 (t, ЗН), 0.88 - 0.82 (t, 6Н), 0.11 - 0.05 (t, 4Н), 0.04 - 0.01 (t, 6Н).

Stage 4: 1-1-(trifluoromethyl)cyclopropyl|propane-1,3-diol 9/one

E (in)

IS

7 o -- hmm E on 5 EE

Add ethyl 3-Igret-butyl(dimethyl)silyl|oxy-3-| to the solution - (trifluoromethyl)cyclopropyl|ipropanoate (3.51 g, 10.310 mmol) in anhydrous tetrahydrofuran (50 ml) was added lithium aluminum hydride (469.57 mg, 0.5121 ml, 12.372 mmol) at 0 "C. The reaction mixture was stirred at 0 "C within 1 hour. The reaction mixture was diluted with diethyl ether (50 ml) and then quenched with water (0.5 ml), sodium hydroxide (0.5 ml) and water (1.5 ml) at 0 C and stirred for 30 minutes. Magnesium sulfate was added and the solid was removed by filtration. The filtrate was concentrated in vacuo and purified by silica gel chromatography using a gradient of 100 95 hexanes to 10095 ethyl acetate to give 1-(1-(trifluoromethyl)cyclopropyl|propane-1,3-diol (1.493 g, 73 90) as a clear liquid. IN NMR (250 MHz, chloroform-4a) b 4.03-3.67 (m, ЗН), 2.83 (d, U - 4.2 Hu, 1Н), 2.16 (s, 1Н) , 1.96-1.74 (m, 2H), 1.13-0.93 (m, 2H), 0.93-0.69 (m, 2H).

Stage 5: tert-butyl 3-3-hydroxy-3-P1-(trifluoromethyl)cyclopropyl|I-propoxy|pyrazole-1-carboxylatone o M o shta tok. o -- (c) nM--Mm - -

E he - A va

EE o

Eee

To a solution of 1-11-(trifluoromethyl)cyclopropyl|Ipropane-1,3-diol (1.493 g, 7.5397 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (1.4582 g, 7.9167 mmol) and triphenylphosphine (3.9550 g, 15.079 mmol) in anhydrous tetrahydrofuran (30 ml) was added OIAO (3.0491 g, 15.079 mmol) dropwise at 0 "C. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water ( 30 mL) and tetrahydrofuran were removed under reduced pressure. The product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, using a gradient from 0 95 to 50 90 ethyl acetate in hexane, to give tert-butyl-3-3-hydroxy-3-H11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate (1.04 g, 37 95) in in the form of a transparent liquid. 1H NMR (250 MHz, Spiogoitogit-a) b 7.84 (y, 9 - 2.9 Hz, 1H), 5.85 (y, 7 - 2.9 Hu, 1H), 4.58 (ada, U - 10.9, 9.4, 3.8 Hz, 1H), 4.37 (a, y - 10.6, 4.6 Hz, 1H), 3.79 (a, U - 10.6 Hz, 1H), 3.70 (5, 1H), 2.31 - 2.07 (t, 1H), 1.97 - 1.75 (t, 1H), 1.60 (5, 9H), 1.06 - 0.68 (t, 4H). MO-IER, etc./2 calc. 350.1453, found 351.1 (M--1) same; Holding time: 4.97 min. (The method of RH O).

Stage 6: tert--butyldimethyl-|3-(1H-pyrazol-3-yloxy)-1-(11-

Zo (trifluoromethyl)cyclopropyl|Ipropoxy|silane o -y o M pad - z

E OH E 0-51

KK

EE

To a solution of tert-butyl-3-3-hydroxy-3-(/1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazole-1-carboxylate (1.04 g, 2.9686 mmol) and 2,6-lutidine (1, 5905 g, 1.7191 mL, 14.843 mmol) in anhydrous dichloromethane (50 mL) was added dropwise igret-butyl (dimethyl)silyl I-chlorofluoromethanesulfonate (3.1387 g, 2.7269 mL, 11.874 mmol) at room temperature. stirred at room temperature for 2 days, then quenched with 1 N hydrochloric acid (50 mL). The two layers were separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.The residue was purified by chromatography on silica gel using a gradient of 0 95 to 30 95 acetone in hexane to give tert-butyldimethyl-|3-(1H-pyrazol-3-yloxy) -1-(1-«(trifluoromethyl)cyclopropyl|Ipropoxy|silane (895.1 mg, 82 95) as a light yellow oil. NMR (250 MHz, DMSO-4ab) b 11. 84 (5, 1H), 7.49 (5, 1H), 5.62 (5, 1H), 4.16 - 3.98 (t, 2H), 3.64 - 3.55 (t, 1H), 2.12 - 1.85 (t, 2H), 1.07 - 0.94 (t, 2H), 0.85 (5, 9H), 0.79 - 0.62 (t, 2H), 0.06 (5,

ZN), -0.02 (5, ZN). MO-IER tp/2 calc. 364.1794, found 365.1 (M'-1)k; Holding time: 6.52 min. (Method РХ 0).

Stage 7: tert-butyl-6-I(3-(3-(tert-butyl(dimethyl)silyl|oxy-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|-2-chloropyridin- C3-carboxylate (c) Х ly av / i ох (c) va

E o-v8i7 | r 05-52 Y -

E EE X- SI M si E o-85

OK

To a solution of tert-butyl-2,b-dichloropyridine-3-carboxylate (378 mg, 1.524 mmol) and tert-butyldimethyl-|3-(1H-pyrazol-3-yloxy)-1-P1-(trifluoromethyl)cyclopropyl To ipropoxysilane (500 mg, 1.372 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (234 mg, 1.693 mmol), followed by 1,4-diazabicyclo|2.2.2-octane (37 mg, 0.3298 mmol). The heterogeneous mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was quenched with ice and stirred for 15 min. The resulting white solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated, and the resulting brown residue was purified by silica gel column chromatography using a shallow gradient of 100 95 hexane to 100 95 ethyl acetate to give tert-butyl 6-I3-I(III-(tert-butyldimethyl)silyl| oxy-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylate (640 mg, 81 95) in the form of a white solid. MO-IER t/72 cal. 575 ,2194, found 576.36 (M--1)k, retention time: 0.85 min (Method RH I).

Stage 8: 6-I3-(3-I-tert-butyl(dimethyl)silyl|oxy-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylic acid o c) sx de So

My-

Ge) yo r.

EE

Kk H

Tert-Butyl 6-I3-I(3-I(tert-Butyldimethyl)silyl|oxy-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylate (640 mg, 1.111 mmol) was dissolved in a premixed mixture of dichloromethane (2 mL) and trifluoroacetic acid (500 μL, 6.490 mmol), and the reaction mixture was stirred at room temperature for 60 min. The reaction mixture was evaporated and the resulting oil was partitioned between ethyl acetate and saturated bicarbonate solution The aqueous part was extracted two more times with ethyl acetate, then the organic layers were combined, washed with saline, dried over sodium sulfate, filtered and evaporated to obtain /6-I3-IZ-I(Etret--butyl(dimethyl)silyl|oxy -3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylic acid (540 mg, 93 95). MSO-IER p/2 calcd. 519.1568, found 520 ,3

Zo (Ma1)x; Holding time: 0.6 min. (Method RH I).

Stage 9: tert-butyl-(45)-4-(3-(6-((6-(3-(3-(tert-butyldimethyl)silyl|oxy-3-H - (trifluoromethyl)cyclopropyl|propoxy|pyrazole -1-yl|-2-chloropyridine-3-carbonyl|sulfamoyl|-2- pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate

Seams IF i- NM 7 -- 6 65 - - still r E 5-8 Z / in p X- y

E o-8i7 M

BE K- Same

6-I3-(3-I-tert-butyl(dimethyl)silyl|oxy-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|-2-chloropyridine-3-carboxylic acid (540 mg, 1.038 mmol) and carbonyldiimidazole (204 mg, 1.258 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether, and dried in vacuo) were combined in tetrahydrofuran (5 mL) and stirred for 2 h at room temperature. Tert-butyl (45 )-2,2-dimethyl-4-(3-(b-sulfamoyl-2-pyridyl)amino|Ipropyl|Ipyrrolidine-i-carboxylate (431 mg, 1.045 mmol) and then 1,8-diazabicyclo/5.4.O01undec -7-ene (800 μL, 5.350 mmol) and the reaction was stirred at room temperature for 14 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to light -brown oil, which was purified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 100 90 ethyl acetate C obtaining tert-butyl (45)-4-I3-C6-C(6-(3-(3-Itret-- butyl(dimethyl)silyl|oxy-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazole-1 -yl|-2-chloropyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (572 mg, 60 95) as a white solid. MO-IER t/72 calc. 913.36066, found 914.5 (M--1) same; retention time: 0.79 min. (Method RH I).

Stage 10: (145)-8-(3-(3-hydroxy-3-|1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6b-thia -3,9,11,18,23-pentaazatetra cyclo|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trione (Compound 295)

Ii M ooo y: Mch M

TO IF SOS lem Mo "xx | y ze Z M. - MAH / dsh-- MN

E o-v8i77 5

KU na wai o vBoSE

Solution of tert-butyl (45)-4-I3-C6-(6-(3-IZ-(tert-butyl(dimethyl)silyl|oxy-3-(1-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl) |-2-chloropyridine-3-carbonyl|sulfamoyl|-2- pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (572 mg, 0.254 mmol) in dichloromethane (4.8 mL) and trifluoroacetic acid (1, 2 ml, 15.68 mmol) was stirred at room temperature for 4 hours. The solvents were evaporated, the residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was removed and dried in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (15 ml), added molecular sieves Z A and the reaction mixture was stirred for 10 min. Then cesium fluoride (301 mg, 1.982 mmol) and potassium carbonate (284 mg, 2.055 mmol) were added, and the reaction mixture was heated

From at 150 7C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite, and saturated ammonium chloride solution was added to the filtrate. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient of 10095 hexanes to 10095 ethyl acetate to give /(145)-8-(3-(3-hydroxy-3-|1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1 N-pyrazol-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5, 7,9,19(23),20-hexane-2,2,4-trione (compound 295) (192 mg, 46 95) as an off-white solid. TIA NMR (400 MHz,

SNiogoiogt-a) 6 9.77 (5, 1H), 8.20 (ad, U - 2.7, 1.1 Gu, 1H), 8.02 (da, U - 8.4, 0.9 Hz, 1H), 7.54 (a, 9 - 7.5 Hz, 1H ), 7.47 (y, 9 2 7.4, 1.1 Hu, 1H), 7.15 (y, 9 - 8.3 Hu, 1H), 6.54 (a, U - 68.2 Hz, 1H), 5.92 (a, 9 - 2.17 Hz, 1H ), 4.70 (5, 1H), 4.57 (ddaa, U - 11.1, 9.1, 4.0, 2.1 Hz, 1H), 4.40 (a, 9 - 10.5, 5.1 Hz, 1H), 3.90 (5, 1H), 3.60 ( aa, U - 10.0, 2.5 Hz, 1H), 3.32 (aa, U - 10.1, 7.4 Hz, 1H), 3.16 (a, U - 13.7 Hz, 1H), 3.08 - 2.94 (t, 1H), 2.53 (8 , U - 11.2 Hu, 1H), 2.28 - 2.16 (t, 1H), 2.11 - 1.89 (t, 2H), 1.70 - 1.49 (t, 1OH), 1.09 - 0.93 (t, 2H), 0.92 - 0.80 (t , 2H). MO-IER t/: calc. 663.24506, found 664.17 (Ma1)xk; Holding time: 1.93 min. (Method of RH B).

Example 101: Preparation of (145)-8-(3-(3-hydroxy-3-(/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab6 -thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2 ,4-trione (diastereomer 1) (Compound 296) and (145)-8-(3 (3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12 ,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20 -hexane-2,2,4-trione (diastereomer 2) (Compound 297)

(9) Ku

ChD7x m? t and | 5 January 1

M - Mo -- 1 I o and M M M water;

And he

Eh oh oh

OM r vra vade

M - Mach o dm M m Mach 5-4 M M Y

Z -) Mn 3 d- Mn

E Nn

E t, n v diakhiegeoteg 1 diaviegeoteg2

Stage 1: (145)-8-(3-(3-hydroxy-3-|1-"trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6-thia-3 ... 1) (Compound 296) and (145)-8-(3-(3-hydroxy-3-

P-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 297) (9) oi yours about dm M M z - i.

And he

E E o o o o (c) M M o ud ks m Moh -47 M m SHE: va - MN vay t- MN

E Nn

E t, n dia diaziegeoteg 1 diaziegeoteg 2 (145)-8-(3-13-hydroxy-3-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-12,12- dimethyl-2A6b -thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trione (187 mg) was subjected to chiral resolution using

NKR chromatography using a Spigai column! Rak Is (250 X 21.2 mm) (particle size 5 μm) with a mobile phase of 38 95 methanol, 62 95 carbon dioxide at 70 ml/min for 8.0 min (injection volume - 500 μl -- 31 mg/ ml in a mixture of acetonitrile:methanol (90:10)) with obtaining as the first eluted diastereomer (145)-8-(3-I3-hydroxy-3-H1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazole-1 -yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (compound 296) (59.2 mg, 32 95) in the form of a white solid; 1H NMR (400

MgHu, DMOO-ab) b 12.50 (5, 1H), 8.21 (a, U - 2.8 Hz, 1H), 7.82 (y, U - 8.2 Hz, 1), 7.58 (ad, y - 8.5, 7.2 Hz, 1H ), 7.05 (a, 9 - 7.1 Hz, 1H), 6.98 (a, U - 8.5 Gu, 1H), 6.92 (y, U - 8.2 Hz, 1H), 6.71 (a, U - 8.5

Hu, 1H), 6.13 (y, U - 2.7 Hz, 1H), 5.23 (y, 9 - 5.7 Hu, 1H), 4.31 (aa, U - 8.2, 5.6 Hz, 2H), 3.92 (y, 9 - 12.8 Hu, 1H), 3.69 (I, U - 7.0 Hu, 1H), 3.17 (a, U - 4.7 Hz, 1H), 2.95 (j, U - 13.2 Hu, 1H), 2.76 - 2.66 (t, 1H), 2.08 (ad, U - 12.4, 7.7 Hz, 2H), 1.82 (4, U - 16.6, 11.7, 6.2 Hz, ЗН), 1.61 (5, ЗН), 1.60 - 1.53 (t, 2Н), 1.52 (5, ZN), 1.30 (Her, 9U - 24.6, 12.0 Hz, 1H), 0.93 - 0.81 (t, 4H); MO-IER, etc./2 calc. 663.24506, found 664.11 (M--1)f; Retention time: 1.94 min. yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19( 23) 20-hexane-2,2,4-trione (diastereomer 2) (compound 297) (57.8 mg, 31 95) as a white solid; 1H NMR (400

MHz, dimethylsulfoxide-46) b 12.51 (5, 1H), 8.21 (y, 9 - 2.7 Hz, 1H), 7.81 (a, Y - 8.2 Hz, 1H), 7.63 - 7.54 (t, 1H), 7.05 (y , 9 - 7.1 Hz, 1H), 6.98 (5, 1H), 6.92 (y, 9 - 8.2 Hz, 1H), 6.71 (a, y - 8.5 Hz, 1H), 6.12 (a, 9 - 2.7 Hz, 1H ), 5.24 (a, 9 - 5.7 Hz, 1H), 4.31 (da, 9 - 7.6, 5.0 Hz, 2H), 3.92 (y, U - 13.3 Hz, 1H), 3.69 (1, 9 - 7.4 Hz, 1H ), 3.17 (a, 9U - 5.0 Gu, 1H), 2.95 (a, U - 13.4 Hz, 1H), 2.69 (j, U - 16.0 Hz, 1H), 2.20 - 2.01 (t, 2H), 1.83 (daa . 1H), 0.87 (y, U - 8.1 Hz, 4H); MO-IER t/: calc. 663.24506, found 664.11 (M'-1) flat; Holding time: 1.94 min. (Method of RH B).

Example 102: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10),6,8,19( 23), 20-hexane-2,2,4-trione (Compound 299) c) r o on V on Ge) r

March 2

Ier 1 M rezer o p pro M o - - -yayatst r He) ryy

Hey her Yi or and MN ; KG. as c) 0-47 and o vier3 and -- | y: o zier 4 di I Sh i Sh r si M si c) c)

M

Same thing about | with and Mn -4 | ME che at 5-47 Me . p 0-7 vier 5 p zierb c) "sh-i- -- 5-A--- g hit p

M o-

J

(in)

M OM te uv ha

VD o o r M M i vir o Dy M m M i

M

Kg

Stage 1: 1,1,2,2-tetradeutero-2-dispiro|2.0.2.1)heptan-7-ylethanol

0 on r r o on (v) -n- --- V r

Lithium aluminum deuteride (2.8120 g, 68.955 mmol) was weighed into a reaction flask placed in an ice water bath under a nitrogen cylinder. Tetrahydrofuran (160 mL) was added slowly.

The mixtures were left with stirring in an ice water bath for 10 min. 2,2-dideutero-2-dispiro(|2.0.2.1|heptan-7-ylacetic acid (10.85 g, 63.326 mmol), separately dissolved in tetrahydrofuran (40 mL)) was rapidly added dropwise through a syringe. The mixture was allowed to warm to room temperature and stirred for 15 h at room temperature.

Then it was re-cooled in an ice water bath. A Rochelle salt solution was added in small portions to quench unreacted lithium-aluminum deuteride. After quenching, more Rochelle solution (200 ml) was added. The mixture was stirred at room temperature for 10 min and the layers were separated. The aqueous layer was extracted with ether (3 x 60 ml).

Then the combined organic layers were washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated at 30 "C, 100 mbar to obtain 1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|)heptane-7 -ylethanol (9.72 g, 97 95, purity 90 95) in the form of a slightly yellow liquid. IN NMR (250 MHz, DMSO-46) 6 1.34 (5, 1H), 0.76 (d, U - 8.6, 7.1 Gu, 4H), 0.67 - 0.53 (t, 2H), 0.53 - 0.33 (t, 2H).

Stage 2: tert-butyl-3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1-carboxylate (c) o r on H ri ris r ft . M tsi sh- r r d-- (c)

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (6.235 g, 33.85 mmol) and 1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|heptan-7-yl -ethanol (5.0 g, 35.15 mmol) in tetrahydrofuran (80 ml) was added triphenylphosphine (9.37 g, 35.72 mmol). Diisopropylazodicarboxylate (7.0 mL, 35.55 mmol) was slowly added dropwise to the mixture over 10 min (exothermic effect noted). The reaction mixture was stirred at room temperature for 2 hours.

Tetrahydrofuran was removed by i.p. massio. The crude product was purified by silica gel chromatography using a shallow gradient from 100 95 hexanes to 20 95 ethyl acetate in hexane to afford tert-butyl-3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.11)heptane-7 - ylethoxy)pyrazole-1-carboxylate (7.4 g, 71 95) in the form of a transparent syrup. TN NMR (400 MHz,

SNiohoyogit-a) b 7.82 (a, U - 2.9 Hz, 1H), 5.84 (a, U - 2.9 Hz, 1H), 1.61 (5, 9H), 1.44 (5, 1H), 0.83 (d, U

Zo - 1.9 Hz, 4H), 0.68 - 0.61 (t, 2H), 0.52 - 0.45 (t, 2H). MO-IER t/: calc. 308.2038, found 309.2 (M--1) same; Holding time: 2.08 min. (Method of RH E).

Stage 3: 3-(1,1,2,2-tetradeutero-2-dispiro(|2.0.2.1|)heptan-7-ylethoxy)-1H-pyrazole (c)

M

M re ra r Ge! 7 tn r. -.Y y y -- shen, -- - hi (in) and r

To a flask containing tert-butyl-3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1-carboxylate (7.4 g, 23.99 mmol) was added dichloromethane (125 ml) and trifluoroacetic acid (45 ml, 584.1 mmol). After 30 min, the mixture was evaporated to dryness and neutralized with saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered and evaporated to give a colorless oil, 3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1)heptan-7-ylethoxy)-1H -pyrazole (4.95 g, 99 95). MO-

IER t/2 calc. 208.15137, found 209.2 (M--1) k; Holding time: 1.46 min. (Method of RH E).

Stage 4: tert-butyl-2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridin-3Z- carboxylate (9) xx UK

M her M - r t 5-0 same uoFa r ? 5-5 M si hit si M toi hit

Tert-butyl 2,6-dichloropyridine-3-carboxylate (6.05 g, 24.38 mmol), 3-(1,1,2,2-tetradeutero-2-dispiro/2.0.2.1|)heptane-7- ylethoxy)-1H-pyrazole (5.04 g, 24.20 mmol) and potassium carbonate (7.4 g, 53.54 mmol) were combined in anhydrous dimethyl sulfoxide (125 mL). 1,4-diazabicyclo(|2.2.2|octane (545 mg, 4.859 mmol) was added and the mixture was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was diluted with water (75 mL) and stirred for 15 minutes. The solid formed filtered, collected, and dried in vacuo overnight. The remaining filtrate was diluted with ethyl acetate and washed with water (3 x 50 mL). The organic layers were combined and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated at The residue was purified by silica gel chromatography using a gradient of 100 F hexanes to 60 95 ethyl acetate in hexane to give a light yellow oil which was dried in vacuo to give a pale yellow solid which was combined with the previously filtered solid , obtaining tert- -butyl /2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|Ipyridin-3 -carboxylate (9.95 g, 98 95). IN NMR (400

MHz, Spiogoitopt-a) b 8.35 (a, y - 2.9 Hz, 1H), 8.19 (a, y - 8.5 Hz, 1H), 7.69 (j, y - 8.4 Hz, 1H), 5.94 (a, 9 - 2.8 Hz, 1H), 1.62 (5, 9H), 1.48 (5, 1H), 0.88 - 0.81 (t, 4H), 0.70 - 0.62 (t, 2H), 0.51 (a, 9 - 10.7, 1.5 Gu, 2H) . MO-IER t/ calc. 419.19138, found 420.2 (M.-1) k; Holding time: 2.58 min. (Method of RH E).

Stage 5: 2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro(2.0.2.1|heptan-7-yl-ethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid o (c) log m - r MV--23 shchi sh-

tert-butyl 2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro(2.0.2.1Iheptan-7-ylethoxy)pyrazole-1-

Zoyl|pyridine-3-carboxylate (13.15 g, 31.31 mmol) was dissolved in dichloromethane (250 mL). Trifluoroacetic acid (50 mL, 649.0 mmol) was slowly added to the mixture and the mixture was continued to stir at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to a solid, which was then suspended in diethyl ether and filtered (2X) to give a solid, which was recrystallized from dichloromethane and collected by filtration to give a white solid (collection 1). The product remained in the dichloromethane filtrate, which was evaporated to give an off-white solid, which was dissolved in ethyl acetate and washed with 5 n. sodium hydroxide (2x), then 1 n. with hydrochloric acid (1x), then dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a C18 column with a reverse phase of 150 g, loading dimethyl sulfoxide and eluting with a gradient from 50 95 to 100 95 acetonitrile in water, obtaining ( after combining with the filtered solid 1 fraction) 2-chloro-6-

IZ-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (9.05 g, 79 95) in the form white solid. NMR (400 MHz, DMSO-ab) b 13.61 (5, 1H), 8.53 - 8.28 (t, 2H), 7.72 (a, U - 8.4 Hz, 1H), 6.17 (a, U - 2.9 Gu, 1H) , 1.46 (5, 1H), 0.87 - 0.79 (t, 4H), 0.68 - 0.61 (t, 2H), 0.53 - 0.45 (t, 2H). MO-IER t/2 calc. 363.12878, found 364.3 (M) k; retention time: 1.45 min. (method RH b).

Stage 6: tert-butyl (45)-4-I3-C(6-C2-chloro-6-(3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1|heptane-7- yl-ethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl- pyrrolidine-1-carboxylate o o o o

M M

M ih Mu y My zhu Ton -- oh oo--Y M o dm Me . Shchi hi and

M M

To a solution of 2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxylic acid (200 mg , 0.5497 mmol) in tetrahydrofuran (1.5 mL), carbonyldiimidazole (110 mg, 0.6784 mmol) (recrystallized from tetrahydrofuran) was added and the mixture was stirred at room temperature for 3 hours, then tert-butyl (45)- 2,2-Dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (240 mg, 0.5818 mmol) as a solution in tetrahydrofuran (500 μl) followed by the addition of 1 . ) (the aqueous layer then had a pH of -1). The layers were separated, and the organic layer was washed with water (1X) and brine (1X), then dried over sodium sulfate, filtered, and concentrated to a white foam, which was purified on a reverse column phase C 18, eluting with a gradient from 50 95-100 95 acetonitrile in water with the formation of tert-butyl (45)-4-I3-((6-Ce-chloro-6-I(3-(1,1,2, 2-tetradeutero-2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (190 mg, 46 95) as an off-white solid. MO-

IER t/2 calc. 757.33264, found 758.3 (M--1) k; retention time: 2.14 min. (Method РХ 0).

Stage 7: (145)-8-I3-(2-I6dispiro|2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazol-1-yl|-12 ,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5(10),6,8,19(23) ,20-hexane-2,2,4-trione (Compound 299)

Oo oo

M o oy hu t 7 s m? with

M 8 Mich | r o dsh- MN or shsh- Mn i I

M ve

Tert-butyl (45)-4-I3-((6-Ce-chloro-6-I(3-(1,1,2,2-tetradeutero-2-dispiro(2.0.2.1|heptane-7-

Z ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2-dimethylpyrrolidine-1-carboxylate (160 mg, 0.2110 mmol) was dissolved in dichloromethane (5 mL ), and trifluoroacetic acid (525 μl, 6.814 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure, 25 ml of toluene was added and removed by rotary evaporation. 25 mL of toluene was added again and removed by rotary evaporation, then dried in vacuo overnight to give a residue which was combined with potassium carbonate (205 mg, 1.483 mmol), molecular sieves ZA and MMP (9.5 mL) in a vial, blown with nitrogen. closed, heated to 155 "C and stirred for 5 hours. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with water (2 X 20 ml), and then with saline. The organic layer was additionally washed with water, dried over sodium sulfate , filtered and evaporated.The residue was purified on a C18 reverse phase column eluting with a gradient of 5095 to 100 95 acetonitrile in water to give material which was then subjected to column chromatography on silica gel using a shallow gradient of 100 95 dichloromethane to 10 95 methanol in dichloromethane, to obtain as an off-white solid, (145)-8-1 H-pyrazol-1-yl|I-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5(10 ),6,8,19(23),20-hexane-2,2,4-trione (compound 299) (79.04 mg, 60 9). TN NMR (400 MHz, dmMso-avb) b 12.51 (5 , 1H), 8.20 (a, 9 - 2.68 Hz, 1H), 7.81 (a, 9 - 8.2 Hz, 1H), 7.57 (AND. U - 7.9 Hz, 1H), 7.05 (a, 9. - 7.1 Hz, 1H), 6.99 (5, 1H), 6.91 (y, 9 - 8.2 Hz, 1H), 6.71 (a, 9 - 8.6 Hz, 1H ), 6.08 (a, 9 - 2.8

Gu, 1H), 3.92 (9, U 2 12.7 Hz, 1H), 3.15 (5, 1H), 2.95 (y, U - 13.3 Hz, 1H), 2.78 - 2.63 (t, 1H), 2.12 (5, 1H ), 1.85 (ai, U - 11.6, 5.2 Hz, 1H), 1.77 (5, 1H), 1.60 (5, 5H), 1.55 (5, 1H), 1.51 (5, ЗН), 1.45 (5, 1H) , 1.30 (a, U - 23.8, 11.4 Hz, 1H), 0.87 - 0.79 (t, 4H), 0.69 - 0.60 (t, 2H), 0.53 - 0.46 (t, 2H). MO-IER t/2 calc. 621.3035, found 622.3 (M--1) xx; retention time: 1.87 min. (Method RK 5).

Example 103: Preparation of (145)-8-I3-(2-Isdispiro(2.0.2.1|Heptan-7-yl)-2,2-didetero-ethoxy)-1H-pyrazol-1-yl|-12,12- Dimethyl(20-deutero)-2A6-thia-3,9,11,18,23-pentaaztetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21- hexane-2,2,4-trione (compound 298) o o Ef sx Kei sx ss v Sh y M su i - Vp -- | M si k - -- for I schi Ole and hi | owls

MU POM

M and M p vier Z sh | ru n HER Zh- vyvr 4 a | vd: ova 08 I " vd y o oo

M IM

N

M 4 es ver 5 - M. 02 r sho M M oter M

Stage 1: tert-butyl (45)-4-3-((3-benzyloxy-6-|(2-chloro-6-I3-(2,2-didetero-2-dispiro|2.0.2.1|heptane-7 -yl-ethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-

From pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate about Y M heny vy uoshch | xx

Gee! zkh o / p em M si x 5-0 8-0-- r ? 5-4 schi te sia in c) with Z sn pcs. about nm hi - on -i-v

2-Chloro-6-I3-(-2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (1.5 g, 4.146 mmol ) and carbonyldiimidazole (831 mg, 5.125 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether, and dried under high vacuum) were combined in tetrahydrofuran (10 mL) and stirred for 2 h at room temperature. Then tert-butyl (4S)-4-3-(3-benzyloxy-6-sulfamoyl-2-pyridyl)amino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (1.5 g, 2.892 mmol) was added. and then 1,8-diazabicyclo/5.4.O01undec-7-ene (3.2 mL, 21.40 mmol), and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a slight gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl (45)-4-3-(3-benzyloxy-6-C(2-chloro-6-

3-(2,2-dideutero-2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl|Isulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine -1-carboxylate (2.2 g, 62 Ob) as an off-white solid. MO-IER t/: calc. 861.36194, found 862.3 (M--1) k; retention time: 0.76 min. (The RH | method).

Stage 2: (145)-20-(benzyloxy)-8-(3-(2-Idispiro|2.0.2.1|heptan-7-yl2,2-dideutero)ethoxy)-1H-pyrazol-1-yl|I- 12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

TO YO

M. - M ikh Vp m. sh- M y Va (9) uk

IN

Solution of tert-butyl (45)-4-3-((3-benzyloxy-6-(2-chloro-6-I3-(2,2-didetero-2-dispiro|2.0.2.1|heptan-7-ylethoxy) pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (2.2 g, 2.551 mmol) in dichloromethane (16 mL) and trifluoroacetic acid ( 4 mL, 52.27 mmol) was stirred at room temperature for 2 h. The reaction solvents were removed by evaporation. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (2 mL), the organic layer was collected and the solvent was removed. The resulting residue was dissolved in dimethyl sulfoxide ( 50 mL) and oven-dried 4 A MB was added, and the mixture was stirred for 10 min. Cesium fluoride (1.2 g, 7.900 mmol) and potassium carbonate (1.1 g, 7.959 mmol) were then added, and the reaction

The mixture was heated at 150 "C for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite, washed with ethyl acetate and saturated ammonium chloride solution was added. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate, filtered and concentrated.The resulting brown residue was purified by silica gel column chromatography using a slight gradient from 100 95 hexanes to 100 95 ethyl acetate to give /(145)-20-(benzyloxy)-8-(3-( 2-Idispiro|2.0.2.1|heptan-7-yl2,2-dideutero)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14,05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (1.26 g, 68 95) as an off-white solid. 1H NMR (400 MHz, Spiogoitogite-a) b 9.99 (5, 1H), 8.19 (a, 7 - 2.7 Hz, 1H), 8.05 (a, U - 8.4 Hz, 1H ), 7.53 (a, U - 8.0 Hz, 1H), 7.47 - 7.36 (t, 5H), 7.27 - 7.23 (t , 1H), 6.98 (y, 9 - 8.1 Hu, 1H), 5.89 (a, U - 2.7 Hu, 1H), 5.30 (y, U - 8.4 Hz, 1H), 5.10 (5, 2H), 4.23 (5 . (5, 1H), 2.14 - 2.05 (t, 1H), 1.62 (I, 9 - 3.2 Hz, 11H), 1.48 (5, 1H), 0.85 (d, U - 2.5 Hz, 4H), 0.71 - 0.60 ( t, 2H), 0.55 - 0.43 (t, 2H). MO-IER t/:2 calc. 725.3328, found 726.45 (MA) k;

Holding time: 0.7 min. (Method RH I).

Stage 3: 0 (145)-8-I3-(2-isdispiro|2.0.2.1|)heptan-7-yl2,2-didetero)ethoxy)-1H-pyrazol-1-yl|- 20-hydroxy-12 ... ,2,4-trione

YO Y U oo dm Mem ovi 77 oo u sa Ya Ton hi o Mn i o Mn

To a stirred solution (145)-20-(benzyloxy)-8-(3-(2-idispiro|2.0.2.1|heptan-7-yl2,2-dideutero)ethoxy)-1H-pyrazol-1-yl|I- 12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23), 20-Hexane-2,2,4-trione (500 mg, 0.6888 mmol) in EUN (10 mL) was added 10 95 palladium on carbon (wet, Oedivza, 155 mg, 0.1456 mmol) under a nitrogen atmosphere. The heterogeneous mixture was stirred with hydrogen cylinders for 2 hours at ambient temperature and the black heterogeneous reaction mixture was filtered through a layer of celite. The filtrate was concentrated under reduced pressure to obtain (145)-8-(3-(2-idispiro|2.0.2.1|heptan-7-yl2,2-didetero)ethoxy)-1H-pyrazol-1-yl|-20-hydroxy - 12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaaztetracycloi|17.3.1.111,14.05,10)|hetracose-1(23),5,7,9,19,21-hexane -2,2,4-trione (156 mg, 36 9o) as a light brown solid. 1TH NMR (400 MGu, DMSOO-ab) b 12.31 (5, 1H), 10.84 (5, 1H), 8.20 (y, U - 2.68 Hu, 1H), 7.76 (a, - 68.2

Hz, 1), 7.07 (a, 9U - 7.7 Hz, 1H), 6.91 (ai, 9 - 9.6, 7.9 Hz, 2H), 6.17 (5, 1H), 6.07 (a, U - 2.7 Hz, 1H), 4.20 (y, 9 - 1.5 Hz, 2H), 3.92 (5, 1H), 3.18 (5, 1H), 2.99 (0, U - 13.1 Hz, 1H), 2.68 (5, 1H), 2.11 (a, - 6.6 Hz, 1H), 1.97 - 1.81 (t, 2H), 1.66 - 1.48 (t, 9H), 1.45 (5, 1H), 1.24 (d, U - 11.7 Hz, 1H), 0.87 - 0.79 (t, 4H ), 0.69 - 0.59 (t, 2H), 0.56 - 0.43 (t, 2H). MO-IER t/: calc. 635.2859, found 636.39 (MAT) k; Holding time: 0.54 min. (The RH | method).

Stage 4: (145)-8-I3-(2-[dispiro(2.0.2.1|heptan-7-yl2,2-didetero)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl -2,2,4-trioxo-2Abthia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10)|tetracose-1(23),5,7,9,19,21 -hexan-20-yl 4-methylbenzene-1 sulfonate (o) 9/j o oy em M ry -0-k o She Mem - otv for АХ for og

To the stirred solution (145)-8-I3-(2-nd (dispiro(2.0.2.1|heptan-7-yl2,2-didetero)ethoxy)-1H-pyrazol-1-yl|20 hydroxy-12,12- dimethyl-2А6-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexaene-2,2 ,4-trione (50 mg, 0.07864 mmol) in anhydrous dichloromethane (2 mL) was added 4-methylbenzenesulfonyl chloride (17.8 mg, 0.09337 mmol), triethylamine (30 μL, 0.2152 mmol) and a catalytic amount of M ,M-dimethylpyridin-4-amine (2.7 mg, 0.02210 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous chloride solution

With ammonium and extracted with ethyl acetate. The combined organic layers were washed with saline, dried over sodium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a slight gradient from 10095 hexanes to 10095 ethyl acetate to give (145)-8-13-(2-yldispiro|2.0.2.1|)heptan-7-yl2,2-dideutero )ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2,2,4-trioxo-2A6-thia-3,9,11,18,23- pentaazatetracyclo!17,3.1.111,14.05 ,10)|htetracose-1(23),5,7,9,19,21-hexan-20-yl 4-methylbenzene-1-sulfonate (36 mg, 58 95) as a white solid. 1H NMR (400 MHz, DMSO-ab) b 12.56 (5, 1H), 8.20 (a, 9 - 2.8 Hu, 1H), 7.92 (a, U - 8.4 Hz, 2H), 7.60 (a, U - 8.3 Hz , 1H), 7.65 (a,

U -8.1 Hu, 1n), 7.47 (a, 9 - 8.2 Hz, 2H), 7.12 (a, 9 - 8.1 Hu, 1H), 6.91 (a, U - 8.2 Hz, 1H), 6.76 (5, 1H) . . 2H), 1.58 (5, ЗН), 1.51 (5, ЗН), 1.48 - 1.32 (t, 4Н), 0.88 - 0.76 (t, 4Н), 0.68 - 0.59 (t, 2Н), 0.54 - 0.40 (t, 2H). MO-IER t/2 calc. 789.29474, found 690.18 (M-a-1)k; Holding time: 0.67 min. (Method RH I).

Stage 5: (145)-8-I3-(2-I(dispiro(2.0.2.1|heptan-7-yl)-2,2-didetero-ethoxy)-1H-pyrazol-1-yl|- 12, 12-dimethyl(20-deutero)-2A6b-thia-3,9,11,18,23-

pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound

OM Ii M

So p vo n o o d sia m M ikhote z o o rs sia m M. ikh o hi -Y MN hi. about MN

Solution (145)-8-I3-(2-idispiro|2.0.2.1|heptan-7-yl2,2-didetero)ethoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl-2,2 ,4-trioxo-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane-20 -yl-4-methylbenzene-1-sulfonate (70 mg, 0.088 mmol) in dry M,M-dimethylformamide (2 mL) was purged with nitrogen for 5 minutes using a balloon. Dichloronickel, triphenylphosphane (15 mg, 0.023 mmol) and tricyclohexylphosphane (18 mg, 0.064 mmol) were then added. The resulting green solution was stirred for 5 minutes under a nitrogen atmosphere and tetradeuteroboranoid (sodium salt) (50 mg, 1.195 mmol) was added in one portion. The resulting dark reddish-brown mixture was stirred at room temperature for 1 hour. Dichloronickel, triphenylphosphane (15 mg, 0.023 mmol), tricyclohexylphosphane (18 mg, 0.064 mmol), and tetradeuteroboranoid (sodium salt) (50 mg, 1.195 mmol) were additionally added, and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethylsulfoxide and filtered through a UuUpaytap disc filter (Rigadiss 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 50 95 to 9995 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile) to obtain (145)-8-I(3-(2-II6dispiro(|2.0.2.1| heptan-7-yl)-2,2-dideutero-ethoxy )-1H-pyrazol-1-yl|-12,12-dimethyl(20-deuterium)-2A6b-thia-3,9,11,18,23- pentaazatetracyclol 1 7.3.1.111,14.05,10)hetracose -1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 298) (22.8 mg, 41 95) as a white solid. TN NMR (400 MHz, DMSO-ab) b 12.51 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 7.81 (a, U - 8.3 Hu, 1H), 7.57 (y, U - 7.3 Hz , 1H), 7.05 (a, U - 7.2 Hz, 1H), 7.00 (5, 1H), 6.91 (0.9 - 8.2 Hz, 1H), 6.08 (a, U - 2.7 Gu, 1H), 4.20 ( , 9U - 1.4 Hu, 2H), 3.92 (0.9 - 12.4 Hz, 1H), 3.16 (5, 1H), 2.95 (y, U - 13.2 Hu, 1H), 2.71 (I, U - 10.8 Hz, 1H ), 2.13 (5, 1H), 1.86 (aa, 9 - 11.6, 5.3 Gu, 1H), 1.77 (5, 1H), 1.60 (5, 5H), 1.51 (5, ЗН), 1.46 (5, 1H) , 1.31 (d, U - 12.6, 12.2 Hu, 1H), 0.90 - 0.78 (t, 5H), 0.68 - 0.62 (t, 2H), 0.53 - 0.46 (t, 2H). MO-IER t/2 calc. 620.29,

From found 621.24 (M--1)x; retention time: 1.3 min. (The method of RH U).

Example 104: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl(20-deutero)- 2Ab6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)|hetracose-1(23),5,7,9,19,21-hexane-2,2, 4-trione (compound 300) (c) i

In t | 5 ek | M M -y he higher /4 (e) 9 (c) m

So to vo uv n 5ieer2

M - M 2 77 j M - M ikh dom M M ote dO M M o for AH for vd;

Stage 1: (145)-8-IZ3-(2-(dispiro(2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2,2,4-trioxo -2A6b-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexan-20-yl 4-methylbenzene -1-sulfonate o oo o oo

M M

5-4 We xx sno 077 5-4 M xx ot5 and -- Mn s w- Mn

To a stirred solution (145)-8-I3-(2--dispiro|(2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-20-hydroxy-12,12-dimethyl-2A6- thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (150 mg, 0.2367 mmol) in anhydrous dichloromethane (3.000 ml) was added A-methylbenzenesulfonyl chloride (58 mg, 0.3042 mmol), triethylamine (80 μl, 0.5740 mmol) and a catalytic amount of M,M-dimethylpyridine-4 -amine (10 mg, 0.08185 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and concentrated. The resulting brown residue was purified by chromatography on silica gel using a slight gradient from 100 95 hexanes to 100 95 ethyl acetate to give (14 5 )-8-I3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazole -1-yl|I-12,12-dimethyl-2,2,4-trioxo-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1( 23),5,7,9,19,21-hexane-20-yl-4-methylbenzene-1-sulfonate (120 mg, 51 95) as a white solid. MO-IER t/2 calc. 787.28217, found 788.42 (M--1) xx; retention time: 1.39 min. (The method of RH U).

Stage 2: (145)-8-I3-(2-isdispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl(20-deuterium)-2A6 -thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 300) о оо о оо

M M and shsh- Mn with shsh- Mn

Solution (145)-8-3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2,2,4-trioxo- 2A6b-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexan-20-yl 4 methylbenzene-1 -sulfonate (120 mg, 0.1523 mmol) in dry M,M-dimethylformamide (1 ml) was purged with nitrogen for 5 minutes using a balloon. Dichloronickel, triphenylphosphane (30 mg, 0.04586 mmol) and tricyclohexylphosphane (34 mg, 0.1212 mmol) were then added. The resulting green solution was stirred for 5 minutes in the atmosphere

Tetradeuteroboranoid (sodium salt) (87 mg, 2.079 mmol) was added in one portion from nitrogen.

The resulting dark reddish-brown mixture was stirred at room temperature for 1 hour. . Dichloronickel, triphenylphosphane (30 mg, 0.04586 mmol), tricyclohexylphosphane (34 mg, 0.1212 mmol), and tetradeuteroboranoid (sodium salt) (87 mg, 2.079 mmol) were additionally added, and the mixture was stirred at room temperature under nitrogen overnight. . The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethylsulfoxide and filtered through a Uupanitap disc filter (Rigadibes 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 50 95 to 99 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile) to obtain (145)-8-I3-(2-

Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl(20-deutero)-2A6-thia- 3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 300) (35 mg, 37 95) in the form white solid. . IN NMR (400 MHz, DMSO-ab) b 12.52 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 7.81 (a, U - 8.2 Hz, 1H), 7.56 (a, U - 7.1 Hz , 1H), 7.04 (a,

U same 7.2 Gu, 1H), 6.98 (5, 1H), 6.90 (a, U - 68.1 Hz, 1H), 6.08 (y, 9 - 2.7 Hz, 1H), 4.25 - 4.17 (t, 2H),

3.92 (a, U - 12.5 Gu, 1H), 3.17 (5, 1H), 2.94 (a, U - 13.2 Hz, 1H), 2.72 (5, 1H), 2.20 - 2.06 (t, 1H), 1.81 (a , U - 6.6 Hz, 4H), 1.60 (5, ЗН), 1.56 (y, У - 13.5 Hu, 2Н), 1.51 (5, ЗН), 1.46 (а, У - 6.5 Hu, 1Н), 1.36 - 1.26 (t, 1H), 1.23 (5, 1H), 0.87 - 0.76 (t, 4H), 0.70 - 0.59 (t, 2H), 0.50 (yes, 9 - 6.0, 4.3 Hz, 2H). MO-

IER t/2 calc. 618.2847, found 619.25 (M--1)k; retention time: 1.28 min. (The method of RH U).

Example 105: Preparation of (145)-8-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazol-1-yl|- 12,12-dimethyl(20-deuterium)-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9, 19,21-hexane-2,2,4-trione (compound 301) o) 9; yam m o o M Y M zi Ma and her M kna M mashe Ka o

M Her KU

M - M ikh vier Z shre ro M zir 4 o i o o o

M 9 ar what else Zh o dom M M Ot5 vyvr3 M - ro o? ts shchi

Stage 1: tert-butyl /(45)-4-I3-(3-benzyloxy-6-C2h-chloro-6-(3-(1,1,2,2-tetradeutero-2-dispiro|2.0.2.1| heptan-7-yl-ethoxy)pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of 2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (500 mg , 1.374 mmol) in dry tetrahydrofuran (5 mL) was added carbonyldiimidazole (207 mg, 1.277 mmol) and the mixture was stirred for 2 hours at room temperature. Tert-butyl (45)-4-3-(3-benzyloxy-6- sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (410 mg, 0.7905 mmol) followed by 1,8-diazabicyclo/5.4.O01undec-7-ene (600 μl, 4.012 mmol), and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), filtered and concentrated. The resulting brown residue was purified by column chromatography with silica gel using a small gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl (4 5)-4-3-((3-benzyloxy-6-|(2-chloro-6-I3- (1,1,2,2-tetradeutero-2-dispiro(2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carbonyl|isolphamoyl|-2-pyridylyamino|Ipropyl|-2,2 -dimethylpyrrolidine-i-carboxylate (436 mg, 37 95) as an off-white foamy solid. MO-IER Ip/2 calc. 863.3745, found

From 864.47 (М-А1)x; retention time: 1.74 min. (Method RH I).

Stage 2: (145)-20-(benzyloxy)-8-(3-(2-idispiro(2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazole -1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10)htetracose-1(22),5,7,9, 19(23),20-hexane-2,2,4-trione shk ik Ya

M. - M and M - M ikh in; (o) |in;

But hee y: hee

Solution / tert-butyl (45)-4-3-((3-benzyloxy-6-(2-chloro-6-I3-(1,1,2,2-tetradeutero-2-dispiro|2,0.2.1 |heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (436 mg, 0.5043 mmol) in trifluoroacetic acid (400 μL, 5.192 mmol) and dichloromethane (1.6 mL) were stirred at room temperature for 2 h. The solvents were evaporated and the resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (2 mL), the organic layer was collected and the solvent was removed . The resulting residue was dissolved in dimethyl sulfoxide (5 mL) and oven-dried 4 A M5 was added, and the resulting mixture was stirred for 10 minutes. Then potassium carbonate (231 mg, 1.671 mmol) was added and the reaction mixture was heated at 140 "C for 16 hours. The reaction mixture was filtered through a UuUpaytap disc filter (25 Te rigadizs) and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 5095 to 9995 roho my phase B within 15.0 min. (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile to obtain (145)-20-(benzyloxy)-8-I3-(2-yldispiro(2.0.2.1|)heptan-7-yl) -1,1,2,2- tetradeuteroethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14 ,05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4--rione (184 mg, 44 95) as an off-white solid. TIA NMR (400 MHz, SPiogoiogite-a) b 9.96 (5, 1H), 8.19 (a, U - 2.8 Hz, 1H), 8.06 (a, 9 - 8.4 Hz, 1Hn), 7.55 (a, 9 - 8.0 Gu , 1H), 7.46 - 7.36 (t, 5H), 7.27 (a, - 8.5 Hz, 1H), 7.00 (a, U - 8.1 Hz, 1H), 5.90 (a, U - 2.68 Hz, 1H), 5.32 ( a, U - 6.3 Hz, 1H), 5.11 (5, 2H), 3.91 (5, 1H), 3.42 - 3.31 (t, 1H), 3.19 (a, U - 14.1 Hz, 1H), 3.05, 7 - 9.7 Hz, 1H), 2.67 (5, 1H), 2.10 (aa, U - 12.2, 8.2 Hz, 1H), 1.62 (5, ЗН), 1.61 (5, ЗН), 1.58 (Bg 5, 4Н), 1.25 ( 5, 1H), 0.85 (d, U t 2.5 Hz, 4H), 0.69 - 0.61 (t, 2H), 0.54 - 0.46 (t, 2H). MO-IER t/:2 calc. 727.3454, found 728.47 (M--1) xx; retention time: 1.43 min. (Method RK 7).

Stage 3: (145)-8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazole-1-ylI-20- hydroxy-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21 -hexane-2,2,4-trione o Ba 9; m

Ч M вх чу M че о m Mch 9, o dm Mch S, cha as cha ul n |c) in |c)

To a stirred solution (145)-20-(benzyloxy)-8-I3-(2-idispiro(2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeuteroethoxy)-1H-pyrazole-1 -yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)tetracose-1(22),5,7,9,19 (23),20-hexane-2,2,4-trione. (184 mg, 0.2528 mmol) in EN (5 mL) was added 10 95 palladium on carbon (wet, Oedivzza, 27 mg, 0.02537 mmol) under a nitrogen atmosphere. The heterogeneous mixture was stirred under a hydrogen atmosphere (from a cylinder) for approximately 2 hours at ambient temperature and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain (145)-8-I3-(2-Isdispiro(2.0.2.1|heptan-7-yl)-1,1,2,2- tetradeuteroethoxy)-1H-pyrazol-1-yl| -20-hydroxy-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9, 19,21-hexane-2,2,4-trione (160 mg, 83,905) as a light brown solid. TN NMR (400 MHz, DMSO-ab) b 12.42 (5, 1H), 11.02 (5, 1H), 8.30 (y, U - 2.7 Hz, 1H), 7.86 (a, U - 68.2 Hz, 1H), 7.17 (0, U) - 7.7 Hz, 1H), 7.06 (a, U - 7.8 Hz, 1H), 7.00 (a, 9 - 8.2 Gu, 1H), 6.27 (5, 1H), 6.18 (y, 9 - 2.8 Hz, 1H), 4.01 (5, 1H), 3.28 (5, 1H), 3.09 (a, U - 12.9 Gu, 1H), 2.86 - 2.69 (t, 1H), 2.22 (5, 1H), 2.01 (5 , 1H), 1.99 - 1.90 (t, 1H), 1.65 (y, U - 34.6 Hz, 9H), 1.55 (5, 1H), 1.40 - 1.28 (t, 1H), 0.97 - 0.89 (t, 4H), 0.77 - 0.70 (t, 2H), 0.62 - 0.53 (t, 2H). MO-IER t/2 calc. 637.29846, found 638.33 (М-а-1)-; retention time: 0.91 min. (The RH method.)).

Stage 4: (145)-8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazol-1-yl|-12 ,12-dimethyl-2,2,4-trioxo-2Abthia-3,9,11,18,23-

pentaazatetracyclo!i17.3.1.111,14.05,10)|tetracose-1(23),5,7,9,19,21-hexan-20-yl 4-methylbenzene-1-sulfonate o z p M bo «4 M vv he bob at 7 M vd o same

To a stirred solution (145)-8-I3-(2-isdispiro(2.0.2.1|heptan-7-yl)-1,1,2,2- tetradeuteroethoxy)-1H-pyrazol-1-yl|-20-hydroxy -12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21- To hexane-2,2,4-trione (160 mg, 0.2107 mmol) in anhydrous dichloromethane (2 mL) was added 4-methylbenzenesulfonyl chloride (45 mg, 0.2360 mmol), triethylamine (60 μL, 0.4305 mmol) and catalytic amount of M,M-dimethylpyridin-4-amine (b mg, 0.04911 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and concentrated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100 95 hexanes to 100 96 ethyl acetate to give (145)-8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)-1,1 ,2,2-tetradeuteroethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2,2,4-trioxo-2A6-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1 .111,14.05,10|hetracose-1(23),5,7,9,19,21-hexan-20-yl 4-methylbenzene-1-sulfonate (147 mg, 88 95) as a white solid. TN NMR (400 MHz, DMSO-46) b 12.51 (5, 1H), 8.14 (5, 1H), 7.85 (a, U - 8.2 Hz, 2H), 7.73 (4.9 - 8.2 Hz, 1H), 7.59 (y, U - 8.0 Hz, 1H), 7.41 (a, 9 - 8.2 Hz, 2H), 7.05 (a, U - 8.0 Hz, 1H), 6.84 (a, y - 8.2 Hz, 1H), 6.70 (5 , 1Н), 6.02 (0.9 -2.7

Hz, 1H), 3.76 - 3.64 (t, 1H), 3.24 (a, 9 - 7.0 Hz, 1H), 2.96 (NK, U - 11.6, 5.3 Hz, 1H), 2.73 (8, U - 13.2

Hu, 1TN), 2.35 (5, ЗН), 2.02 - 1.92 (t, 1Н), 1.79 (I, U 2 11.9 Hu, 2Н), 1.52 (5, 4Н), 1.45 (5, ЗН), 1.39 (5 , 1H), 1.34 (0, 9) - 12.1 Hz, 2H), 1.19 (a, U - 12.7 Hz, 1H), 0.76 (I, U - 3.5 Hz, 4H), 0.57 (ai, U - 8.1, 4.4

Hz, 2H), 0.43 (y, 9 -9.2 Hz, 2H). MS-IR t/2 calc. 791.3073, found 792.17 (Ma1)k; Holding time: 0.65 min. (Method RH I).

Stage 5: (145)-8-I3-(2-I6dispiro|2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeutero-ethoxy)-1H-pyrazol-1-ylI-12, 12-dimethyl(20-deuterium)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19, 21-hexane-2,2,4-trione (compound 301) in; her M » in M o» at 5-47 se Mesa oo Mn hi -- Mn or |c) o |c)

Zo Solution (145)-8-3-(2-isdispiro(2.0.2.1|heptan-7-yl)-1,1,2,2-tetradeuterethoxy)-1H-pyrazol-1-yl|I-12,12 -dimethyl-2,2,4-trioxo-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19 ,21-Hexan-20-yl-4-methylbenzene-1-sulfonate (145 mg, 0.1831 mmol) in dry M,M-dimethylformamide (2 mL) was purged with nitrogen for 5 minutes using a balloon. Dichloronickel, triphenylphosphane (42 mg, 0.06420 mmol) and tricyclohexylphosphane (46 mg, 0.1640 mmol) were then added. The resulting green solution was stirred for 5 minutes under a nitrogen atmosphere and tetradeuteroboranoid (sodium salt) (108 mg, 2.580 mmol) was added in one portion. The resulting dark reddish-brown mixture was stirred at room temperature for 1 hour. Additionally, dichloronickel was added; triphenylphosphane (42 mg, 0.06420 mmol), tricyclohexylphosphane (46 mg, 0.1640 mmol), and tetradeuteroboranoid (sodium salt) (108 mg, 2.580 mmol), and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethylsulfoxide and filtered through a UuUpaytap disc filter (Rigadiss 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 50 95 to 9995 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B -

acetonitrile) to obtain (145)-8-3-(2-ydispiro(2.0.2.1|heptan-7-yl)-1,1,2,2- tetradeuteroethoxy)-1H-pyrazol-1-yl|-12, 12-dimethyl(20-deuterium)-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19, 21-Hexane-2,2,4-trione (compound 301) (26.9 mg, 24 95) as a white solid. 1H NMR (400 MHz, DMSOSO-ab) b 12.60 (5, 1H), 8.30 (a, 9 - 2.8 Hz, 1), 7.91 (a, 9 - 8.2 Hu, 1H), 7.70 - 7.66 (t, 1H) . (a, 9 - 12.1 Hz, 1H), 3.26 (a, U - 6.9 Gu, 1H), 3.05 (a, U - 13.2 Hz, 1H), 2.83 - 2.76 (t, 1H), 2.20 (a, U - 19.9 Hu, 1H), 1.99 - 1.93 (t, 1H), 1.87 (5, 1H), 1.70 (5, 6H), 1.61 (5, ЗН), 1.55 (5, 1H), 1.46 - 1.37 (t, 1H ), 0.97 - 0.90 (t,

AN), 0.76 - 0.72 (t, 2H), 0.63 - 0.57 (t, 2H). MO-IER t/2 calc. 622.3098, found 623.26 (Ma1) xx; retention time: 1.3 min. (The RH method).

Example 106: Preparation of 11-(3-(-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-17Abthia-2,8,10,16,22-pentaazatetracyclo|16.3 .1.15,8.09,14Itricose-1(21),9(14),10,12,18 (22),19-hexane-15,17,17-trione (Compound 1) (o) (c) (9) o ier 1 zier2 zier 1

ЩХЯМ, to you with the same VM YALEzhoVpm of faith

He saw 5

VIM VIM MN zerb NM xx --zhdya 2 with Mn,

M -NSII - 2NSЙ o on M. ivos M. Vos mem Zh v /y M zir 7 fot ver o / y hu o vivr 9 no -- --kzhk sh- -- liny piky v vo

SI M SI o (c)

And KU

What Y ier 10 What Y NA still Cher 11 rozer - zer 5-4 y Y t (in) t schi 7 your x / -- , / - E o Her M

KU Khr zy i" u/ofya | z zer ta m 2 y y r - NM mn, 7-7 ia m si y t kv M u ya-( lk gadi

Stage 1: 1-benzyl-5,5-dimethylpyrrolidin-2-one (c) (c)

VIM 7 with VIM 7 5,5-dimethylpyrrolidin-2-one (19.6 g, 0.174 mol) was dissolved in M,M-dimethylformamide (100 ml) and cooled to 0 "C with subsequent slow addition of Man (10.4 g , 0.261 mol.) The reaction mixture was stirred for 10 minutes, after which benzyl chloride (22 mL, 0.19 mol) was added.

The reaction mixture was allowed to warm to 21 "C for 16 hours. The reaction was quenched by the addition of saturated aqueous MH4ACi followed by the addition of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried over sodium sulfate , filtered and concentrated. The crude product was purified by rapid filtration through a layer of silica (20 95 ethyl acetate in heptane),

yielding pure 1-benzyl-5,5-dimethylpyrrolidin-2-one (30 g, 85 95) as a colorless oil. 1 N

NMR (300 MHz, SOSIZ): 6 7.3 (t, 5Н); 4.4 (5, 2H); 2.42 (I, 2H); 1.9 (, 2H); 1.1 (5, 6H).

Stage 2: 1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate 19) (c) (c)

VIM / w SCHI In h

Diisopropylamine (27.6 ml, 197 mmol) was dissolved in tetrahydrofuran (200 ml) under a nitrogen atmosphere and cooled to -78 °C. n-VIII and (79 ml, 197 mmol, 2.5 M solution in hexane) were added dropwise. and stirring was continued for another 90 min, giving the opportunity to warm up to -20 76.

The reaction mixture was again cooled to -78 "C and 1-benzyl-5,5-dimethylpyrrolidin-2-one (20 g, 98.4 mmol) dissolved in tetrahydrofuran (20 ml) was added, maintaining the temperature below -78706. Stirring was continued for another 1 hour, after which the temperature was adjusted to -80 °C and dimethyl carbonate (17.4 ml, 206.6 mmol) was added. The reaction mixture was allowed to warm to -2070. Water (20 ml) was added slowly, followed by the addition of 4 n. aqueous hydrochloric acid (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 ml).

The combined organic layers were washed with saline, dried over sodium sulfate, filtered and concentrated. Pure /methyl-1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate (7.8 g, 30 95) was obtained as a yellow oil after chromatographic purification on silica gel (40 95 ethyl acetate in heptanes). IN NMR (300 MHz, SOSIZ): a 7.3 (t, 5Н); 4.4 (44, 2H); 3.8 (5, ZN); 3.6 (1, 1H); 2.2 (t, 2H); 1.2 (5, ZN); 1.1 (5, ZN).

Step 3: 2-(1-benzyl-5,5-dimethylpyrrolidin-3-ylacetonitrile (c) (c)

VIM zo t ote

Lithium aluminum hydride (4.2 g, 110.4 mmol) was suspended in tetrahydrofuran (100 ml) and cooled to 0 °C, followed by the dropwise addition of methyl 1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate ( 7.8 g, 29.8 mmol), dissolved in tetrahydrofuran (20 ml).

The reaction mixture was allowed to warm to 20 "C for 16 h, quenched with water and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were dried over sodium sulfate and concentrated. Crude (1-benzyl-5,5-dimethylpyrrolidine-3- il) methanol (6.6 g, quantity) was used without additional purification at the next stage. NMR (300 MHz, SOSIS): a 7.3 (t, 5H); 3.8 (9, 1H); 3.5 (t, 2H) 3.2 (9, 1H); 2.8 (p5, 1H); 2.6 (t, 2H); 2.2 (t, 1H); 1.9 (t, 1H); 1.6 (t, 1H); 1.3 (5, ЗН); 1.03 (5, ZN).

Stage 4: 2-(1-benzyl-5,5-dimethylpyrrolidin-3-ylacetonitrile)

M

(1-Benzyl-5,5-dimethylpyrrolidin-3-yl)methanol (5 g, 22.8 mmol) was dissolved in tetrahydrofuran (60 ml) and cooled to -23 "С with the subsequent addition of EIZM (4.74 ml, 34 .2 mmol) and M5Cl (2.1 mL, 27.4 mmol). The reaction mixture was stirred at this temperature for 15 minutes, then the cooling bath was removed and stirring was continued for another 30 minutes. Water was added, followed by ethyl acetate. The layers were separated and aq. layer was washed with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude material was further dissolved in dimethyl sulfoxide (40 mL) and sodium cyanide (1.7 g, 34.2 mmol) was added. The residue was stirred at 60 "C for 5 hours, after which another amount of sodium cyanide (770 mg) was added and stirring was continued for another 5 hours. The reaction mixture was cooled, water was added, and then ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated. Pure 2-(1-benzyl-5,5-dimethylpyrrolidine-3-ylluacetonitrile)

(Z g, 58 95) was obtained as a yellow oil after purification by chromatography on silica gel (30% ethyl acetate in heptanes). IN NMR (300 MHz, SOSIZ): a 7.3 (t, 5Н); 3.7 (а, 1Н); 3.4 (а, 1Н); 2.78 (i, 1H); 2.4 (t, 2H); 2.0 (t, 1H); 1.6 (t, 2H); 1.2 (5, ZN); 1.05 (5, ZN).

Step 5: 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)/ethan-1-amine hydrochloride

VIM VIM Mn that ЗНШ2Ш0Ю5-

M

"Not

Lithium aluminum hydride (1.25 g, 32.8 mmol) was suspended in tetrahydrofuran (30 mL) and cooled to 0 °C followed by the slow addition of 2-(1-benzyl-5,5-dimethylpyrrolidine-3-ylluacetonitrile (3 g, 13 .1 mmol) was dissolved in tetrahydrofuran (5 ml). The reaction mixture was allowed to warm to 20 "C for 15 hours. The reaction was quenched with water (20 ml) and 1595 aqueous sodium hydroxide (10 ml). The resulting precipitate was filtered through a layer of celite. The precipitate on the filters were washed with ethyl acetate and the layers were separated.The organic layer containing the crude amine was concentrated and the residue was treated with 4N hydrochloric acid in dioxane, then evaporated to give pure 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl) hydrochloride of ethan-1-amine (3.8 g, 98 95) as a yellowish solid. 1H NMR (300 MHz, 020): a 7.4 (t, 5H); 4.4 (t, 1H); 3.9 (t, 1H) ; 3.6 (t, 1H); 3.4 apa 3.0 (t, 1H); 2.8 (t, 2H); 2.6 (t, 1H); 2.2 (t, 1H); 1.6 (t, 1H); 1.42 (5, ЗН ); 1.3 (5, ZN).

Stage 6: 2-(5,5-dimethylpyrrolidin-3-yl)ethan-1-amine dihydrochloride

Vpm Mn, Vim MN, -- "Not "NOI

To a solution of 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)ethan-1-amine hydrochloride (1 g, 3.720 mmol) in methanol (10 mL) was added palladium hydroxide (653.0 mg, 0.9300 mmol) and hydrochloric acid (155.0 μl 6 M, 0.9300 mmol). Air was pumped out of the reaction flask and washed with H2, using a balloon with a three-way adapter, and repeated three times. It was stirred in an H2 atmosphere at room temperature for 48 hours. The reaction mixture was filtered through a layer of celite and the layer was washed with methanol. The filtrate was evaporated to give 2-(5,5-dimethylpyrrolidin-3-yl)uthanamine dihydrochloride (557 mg, 70,965). MO-IER t/72 calc. 142.147, found 143.2 (Ma1)x; Holding time: 0.09 min. (Method of RH A).

Stage 7: tert-butyl 3-(2,2-dimethylpropoxy)pyrazole-1-carboxylate

ON M. Vos Myto d

2,2-Dimethylpropan-i-ol (21.06 g, 238, 9 mmol) and triphenylphosphine (62.66 g, 55.35 ml, 238.9 mmol). OIAO (48.31 g, 47.04 mL, 238.9 mmol) was added dropwise to the mixture, allowing the mixture to gradually warm to 45 °C. After the addition, the mixture was heated at 50 °C for 5 h. The mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 200 mL of ethyl acetate, and the organic phase was washed with 500 mL of 1 N sodium hydroxide, 500 mL of brine, dried over magnesium sulfate, filtered through celite, and concentrated in vacuo to a volume of approximately 300 mL.

Crystallization of triphenylphosphine oxide began, and the light-colored suspension was left overnight.

The suspension was filtered using a medium frit and washed three times with 100 ml of a mixture of 5095 ethyl acetate/hexanes. The filtrate was concentrated by massio. The crude pink oil was diluted with dichloromethane and chromatographed on a 750 g silica gel column, eluting with a 0-25 95 ethyl acetate/hexanes gradient. The collected impure fractions were re-chromatographed on a 330 g silica gel column, eluting with a mixture of 0-25 95 ethyl acetate/hexanes. Pure fractions from both columns were combined and concentrated to give tert-butyl-3-(2,2-dimethylpropoxy)pyrazole-1-carboxylate (45.8 g, 83 95). "IN NMR (400 MHz, Spiogoitopt-a) b 7.83 (y, U - 3.2 Hz, 1H), 5.88 (y, 9 - 3.2 Hu, 1H), 3.95 (5, 2H), 1.62 (0, 9U - 2.2 Hz, 9H), 1.01 (a, U - 2.7 Hz, 9H). MO-IER t/2 calc. 254.16304, found 199.1 (M--1-1Vy) k; Retention time: 1.89 min. (Method RH B) .

Stage 8: 3-(2,2-dimethylpropoxy)-1H-pyrazole

M in Vos M for A ---shft riny pc

To tert-butyl-3-(2,2-dimethylpropoxy)pyrazole-1-carboxylate (111 g, 436.4 mmol) in dichloromethane (450 mL) and methanol (450 mL) was added hydrochloric acid (330 mL of 4 M in dioxane , 1.320 mol) (gradual exothermic effect up to -- 35 C) and the mixture was stirred at 45 rpm for 1 hour. The solvent was removed by vacuum and the residue was diluted with MTBE (900 mL) and washed with sodium hydroxide (650 mL of 2 M, 1,300 mol). The aqueous phase was extracted with 500 ml

MTBE, and the combined organic phases were washed with 800 ml of brine, dried over magnesium sulfate, filtered and concentrated in bulk, obtaining 3-(2,2-dimethylpropoxy)-1H-pyrazole (65 g, 97 95). "IN NMR (400 MHz, DMSOO-ab) b 11.81 (5, 1H), 7.48 (a, 9U - 2.5 Gu, 1H), 5.65 (I, 9 - 1.9 Hz, 1H), 3.70 (5, 2H), 0.96 (5, 9H). MO-IER t/2 calcd 154.11061, found 155.1 (M--1) k, retention time: 1.48 min (Method Х 0).

Stage 9: tert-butyl 2-chloro-6-I3-(2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylate (6) (6) k. ХК р (c) LA xx o xx o from new - M. -

SI M SI A M SI

To tert-butyl-2,6-dichloropyridine-3-carboxylate (12.75 g, 51.39 mmol) and 3-(22-dimethylpropoxy)-1H-pyrazole (7.925 g, 51.39 mmol) in M,M- potassium carbonate (9.232 g, 66.80 mmol) and 1,4-diazabicyclo(|2.2.2)octane (864.6 mg, 7.708 mmol) were added to dimethylformamide (95.10 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at at room temperature for 18 hours. The finely dispersed suspension was diluted with water (95.10 ml), which led to the precipitation of a resinous substance, which began to harden. The mixtures were allowed to settle and the clear solution was decanted from the solid resinous substance. The solid was diluted with 200 ml of water and 25 ml of isopropyl alcohol. The mixture was heated to a homogeneous state of the solution. The mixtures were allowed to cool, and then placed in an ice bath, obtaining a cream-colored semisolid. The solid was collected using a medium frit and washed three times with 10 mL of water. The solid was air-dried for 18 hours to give tert-butyl-2-chloro-6-|3-(2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylate (18 g, 9595). 1H NMR (400 MGu, dmMso-ab) b 8.41 (a, U - 2.9 Hz, 1H), 8.30 (a, U - 8.4 Hz, 1H), 7.73 (a, U - 8.4 Hz, 1H), 6.22 (a , 9 - 2.9

Hz, 7TN), 3.92 (5, 2Н), 1.57 (5, 9Н), 1.01 (5, 9Н). MO-IER tp/2 calc. 365.1506, found 366.2 (MA) k; retention time: 3.53 min. (Method РХ 0).

Step 10: 2-chloro-6-(3-(2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (c) (c) to to -----A

Coo)

To tert-butyl 2-chloro-6-(3-(2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxylate (18 g, 49.20 mmol) in a solution of isopropyl alcohol (90.00 ml) aqueous hydrochloric acid solution (41.00 mL 6 M, 246.0 mmol) was added and the mixture was heated under reflux for 90 min (oil bath temperature 100). The mixture was allowed to cool to ambient temperature and then diluted with water (90 .00 ml). The suspension was cooled slightly in an ice-water bath and the precipitate was collected using a medium-sized frit. The precipitate was washed 3 times with 10 ml of water and dried under vacuum at 45 "C for 2 days to give 2-chloro-6-I3- (2,2-dimethylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (12.72 g, 83 96). NMR (400 MHz, DMSO-ab) b 13.62 (5, 1H), 8.42 (a , U - 2.9 Hu, 1H), 8.38 (a, U - 8.4 Hz, 1H), 7.74 (a, U - 8.4 Hu, 1H), 6.22 (a, U - 2.9 Hz, 1H), 3.93 (5, 2H ), 1.01 (5, 9H). MO-IER t/2 calc. 309.088, found 310.2 (M.-1) k; retention time: 2.61 min. (Method РХ 0).

Step 11: 2-Chloro-6-N3-(-2,2-dimethylpropoxy)pyrazol-1-yl|-N-(b-fluoro-2-pyridyl)sulfonyl|pyridine-3-carboxamide

Y B s U uva: also | in Y iv em MU s y ul 0-Y m si z a Y -- - I

2-Chloro-6-I3-(2,2-dimethylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (1.0 g, 3.228 mmol) and carbonyldiimidazole (785, 1 mg, 4.842 mmol). N,M-dimethylformamide (9.615 mL) was added, and the mixture was stirred at 45 °C under nitrogen for 1 hour. In a separate 40 mL vial, a solution of 6b-fluoro-2-pyridinesulfonamide (682.5 mg, 3.874 mmol) was dissolved in anhydrous M,M-dimethylformamide (9.615 mL) under nitrogen. Sodium hydride (154.9 mg, 3.874 mmol) (60 95 oil suspension) was added portionwise and the mixture was stirred under nitrogen until gas evolution ceased. The vessel was capped and stirred at 45 "C for 45 minutes. The two mixtures were combined and stirred at room temperature for 2 hours. Water and ice were added. Concentrated hydrochloric acid was added dropwise until a white precipitate appeared, then washed with ethyl acetate (2X), the organic layers were combined, dried (sodium sulfate), filtered and concentrated to a yellow residue. The residue was dissolved in ethyl acetate and washed 1:1 with saturated aqueous sodium bicarbonate/1 N. sodium hydroxide (Zh), dried over sodium sulfate, filtered and concentrated. The material was further purified by chromatography on silica gel using a gradient of 100 95 hexanes to 100 95 ethyl acetate to isolate /2-chloro-6-(3-(2,2-dimethylpropoxy)pyrazol-i-yl /I) as a pale yellow foam. -M-(b-fluoro-2-pyridyl)sulfonyl|pyridine-3-carboxamide (1.01 g, 67 95). NR NMR (400 MHz, DMSO-ab) b 8.36 (a,

U 2.8 Hu, 1H), 8.21 - 8.10 (t, 2H), 7.89 (y, U - 5.7 Hu, 1H), 7.65 (y, U - 8.3 Hz, 1H), 7.30 (a, 9 2 7.1

Hu, 1H), 6.15 (a, U - 2.68 Hu, 1H), 3.92 (5, 2H), 1.00 (5, 9UN) MO-IER t/2 calc. 467.08304, found 468.2 (M--1) flat; Holding time: 1.92 min. (Method of RH E).

Stage 12: 11-I3-(-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7,7-dimethyl-1 7Abthia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15, 8.09,14|tricose-1(21),9(14),10,12,18(22),19-hexane-15,17,1 7-trione (Compound 1) 5 5 po n I ni Mn, | n I

Y MA tv |v y slya t o Uk kavy iv zo es zaso

In a vial with a volume of 5 ml, 2-chloro-6-I3--2,2-dimethylpropoxy)pyrazol-1-yl|-M-((6-fluoro-2-pyridyl)sulfonyl|pyridine-3- carboxamide (330 mg, 0.6065 mmol) in dimethyl sulfoxide (2.980 mL), potassium carbonate (419.2 mg, 3.033 mmol) and 2-(5,5-dimethylpyrrolidin-3-yl)ethanamine dihydrochloride (108.4 mg, 0.504 mmol). The vessel was closed with a lid and heated to 120 C on a hot plate for 20 hours. Additional 2-(5,5-dimethylpyrrolidin-3-yl)ethanamine dihydrochloride (108.4 mg, 0.504 mmol) was added and heated to 125 " C on a hot stove for 24 hours.

The reaction mixture was filtered and then purified directly by reverse-phase preparative chromatography using a C18 column (10-99 acetonitrile-water in 5 mM hydrochloric acid) to give an off-white solid, to which was added an excess of potassium carbonate (419.2 mg , 3.033 mmol) and dimethylsulfoxide (2.980 mL), and the mixture was heated for 18 h at 155°C. The reaction mixture was filtered and then purified directly by reversed-phase preparative chromatography using a C18 column (10-99 acetonitrile-water, 5 mM hydrochloric acid) with obtaining as a more polar regioisomer 11-(3-(2,2-dimethylpropoxy)-1H-pyrazol-1-ylI-7,7-dimethyl-17A6-thia-2,8,10,16, 22-pentaazatetracyclo|16.3.1.15,8.09,14)gricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione (compound 1) (34 .5 mg, 1095) in the form of a pale yellow solid. IN NMR (400 MHz, DMSO-ab) 5 12.45 (5, 1H), 8.27 - 8.16 (t, 1H), 7.74 (a, 9 - 30.7 Hz, 2H), 7.17 (4.9 - 6.1 Hz, 1H), 6 .96 - 6.88 (t, 1H), 6.88 - 6.74 (t, 1H), 6.17 - 6.10 (t, 1H), 3.89 (5, 2H), 3.61 (yes, U - 15.1, 8.4 Gu, 1H), 3.35 (5, 1H), 2.48 - 2.29 (t, 1H), 2.25 (5, 1H), 1.91 (aa, U - 10.8, 5.3 Hz, 2H), 1.56 (5, 6H), 1.50 (5, 1H), 1.43 - 1.28 (t, 1H), 1.19 (yes, 9 - 30.9, 7.8 Hz, 1H), 1.00 (5, 9H). MO-IER t/ cal. 553.24713, found 554.2 (M--1)k; Holding time: 2.14 min. (Method of RH E).

Example 107: Preparation of 11-(3-(-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-17Abthia-2,8,10,16,22-pentaazatetracyclo|16.3 .1.15,8.09,14|Itricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione (enantiomer 1) (compound 2) and 11- (3-(-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7,7-

dimethyl-1 7Abthia-2,8,10,16,22-pentaazatetracycloiY16.3.1.15,8.09,14|tricosa- 1(21),9(14),10,12,18(22),19-hexane- 15,17,17-trione (enantiomer 2) (compound 3)

TYA y i DOM o How M m es o Yam M m this i o uk M m -ei aloe uko t i ot

Stage (1:00/11-I3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7,7-dimethyl-17Abthia-2,8,10,16,22- pentaazatetracyclo|16.3. 1.15,8.09,14|tricose-1(21),9(14),10,12,18(22),19-hexane-15,17,1 7-trione (enantiomer 1) (Compound 2) and 11- I(I3--2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-1 7Abthia- 2,8,10,16,22-pentaazatetracyclo|16.3.1.15,8.09,14Itricose- 1(21),9(14),10,12,18 (22),19-hexane-15,17,17-trione (enantiomer 2) (Compound 3)

I 54 HER 54 HER 54 o I M m -- o I 4 m she o uk M m es

Racemic | 11-I3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7,7-dimethyl-17Abthia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15,8.09,14 |trichose-1(21),9(14),10,12,18(22),19-hexane-15,17,1 7-trione (28.4 mg) was subjected to chiral purification by NCRC using SpPigaIRak A5-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 2895 methanol/72 95 carbon dioxide at 10 ml/min, obtaining 11-I(3-(2,2-dimethylpropoxy)-1H) as the first eluted enantiomer -pyrazol-1-ylI|-7,7-dimethyl-1 7Abthia-2,8,10,16,22- pentaazatetracyclo(|16.3.1.15,8.09,14|tricose-1(21),9(14), 10,12,18(22),19-hexane-15,1 7,1 7-trione (enantiomer 1) (compound 2) (4.4 mg, 32 905), MSO-IER t/2 resolution 553, 24713, found 554.2 (Mat) k;

Retention time: 2.14 min (RCH E method); and as the second eluted enantiomer 11-I(3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-1 7Ab-thia-2,8,10,16,22 - pentaazatetracyclo|16.3.1.15,8.09,14|tricose-1(21),9(14),10,12,18.(22),19-hexane-15,17,1 7-trione (enantiomer 2) ( compound 3) (5.6 mg, 41 95), MSO-IER t/2 resolution 553.24713, found 554.2 (Mat) k;

Retention time: 2.15 min (method RH E).

Example 108: Preparation of 7,7-dimethyl-11-(3-11-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo |16.3.1.1(5,8).0(9,14))gricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione ( Compound 4)

І B y on ny 7 vyvri m sce si I - c) di I ge o oy (9) oy os -. SOS

N | NM mn, vier2 | N

In / "I know, NN

Es and vl dk

Stage 1: 2-chloro-M-|((6-fluoro-2-pyridyl)sulfonyl|-6-I3-(11-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridin-3-carboxamide (9 ) (9) Kui U m - t M M ME che Myh tm M si 0-47 da | shchi ; ve Es

A solution of 2-chloro-6-I3-(P1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridin-3-carboxylic acid (3.5 g, 9.386 mmol) and carbonyldiimidazole (2.283 g, 14.08 mmol) ) in dimethylformamide (32.64 ml) was stirred at 60 "C for 60 min and a separate solution of b-fluoro-2-pyridinesulfonamide (1.984 g, 11.26 mmol) and sodium hydride (450.4 mg, 11.26 mmol) in dimethylformamide (32.64 ml) was stirred at 45"C for 45 minutes. The two solutions were combined and stirred at 60"C for 1 hour. Cooled to room temperature and poured into water. Concentrated hydrochloric acid was added dropwise until a white precipitate remained, then washed with ethyl acetate (2X), combined organic layers, dried (sodium sulfate), filtered and concentrated to a white solid.Dissolved in ethyl acetate and washed 1:1 with saturated aqueous sodium bicarbonate/1N sodium hydroxide ( 3x), dried (sodium sulfate), filtered and concentrated to an off-white foam. Stirred in ether and removed the ether under reduced of pressure. The residue was dissolved in a minimum amount of warm dichloromethane, left for 5 minutes, then cooled to 4 °C overnight. The white solid mass was filtered and washed with dichloromethane. The filtrate was converted to a yellow solid, dissolved in a minimum amount of warm dichloromethane and slowly cooled to 4 "With during the night. The resulting mass of white solid was filtered and washed with dichloromethane, obtaining 2-chloro-M-(6-fluoro-2-pyridyl)sulfonyl|-6-(3-(1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl| pyridine-3-carboxamide (3.339 g, 62 95). MO-IER t/2 calcd. 519.86, found 520.2 (M.-1) g; retention time: 1.75 min. (Method RH B) .

Stage 2: 7,7-dimethyl-11-(3-111-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo(| 16.3.1.1(5,8).0(9,14))tricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione (Compound 4) 9 oo 9 oo

M KY

N | nm mn, | N I una Y Yu tzne ry d- d- n g I g

In a vial with a volume of 5 ml, 2-chloro-M-(6b-fluoro-2-pyridyl)sulfonyl|-6-I3-(1-(trifluoromethyl)cyclopropyl|methoxy|pyrazol-1-yl|pyridin- 3-carboxamide (400 mg, 0.7310 mmol) in dimethylsulfoxide (3.040 mL), followed by potassium carbonate (505.1 mg, 3.655 mmol) and 2-(5,5-dimethylpyrrolidin-3-yl)uethanamine dihydrochloride (137, 2 mg, 0.64 mmol). The vial was capped and heated to 75 °C on a hot plate for 92 hours, then for 20 hours at 125 °C.

The reaction mixture was filtered and then purified directly by reverse-phase preparative chromatography using a C18 column (10-99 acetonitrile-water and 5 mM hydrochloric acid) to give the product isolated as a yellow-brown solid, 7,7-dimethyl- 11-(3-C11-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo|16.3.1.1(5,8). 0(9,14))gricose-1(21),9(14),10,12,18 (22),19-hexane-15,17,1 7-trione (compound 4) (35.2 mg, 9 95). IN NMR (400 MHz,

From dmMso-ab) b 12.43 (5, 1H), 8.43-8.41 (t, 1H), 8.21 (a, U - 2.68 Hu, 1H), 7.74 (a, U - 33.4 Hz, 2H), 7.17 (a, 9 - 7.0 Hz, 1H), 6.91 (y, U - 8.2 Hz, 1H), 6.82 (5, 1H), 6.15 (a, U - 2.7 Hz, 1H), 4.37 (d, U - 11.9 Hz, 2H) . (a, 9 - 3.5 Hz, 1H), 1.55 (5, 6H), 1.48 (y, U - 11.0 Gu, 1H), 1.34 (a, U - 12.7 Hz, 1H), 1.18 (a,

U - 11.68 Hu, 1H), 1.11 - 1.06 (t, 4H). MO-IER t/2 calc. 605.2032, found 606.2 (M-1)k; retention time: 2.02 min. (Method of RH E).

Example 109: Preparation of 7,7-dimethyl-11-(3-11-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo |16.3.1.1(5,8).0(9,14))gricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione ( enantiomer 1) (compound 5) and 7,7-dimethyl-11-(3-(1-trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-1 7A6-thia-2,8,10 ,16,22- pentaazatetracyclo|16.3.1.1(5,8).0(9,14))gricose-1(21),9(14),10,12,18(22),19-hexane-15, 17,17-trione (enantiomer 2) (Compound 6)

І B ІІІ Ba І B

Mom ka Mykh M KE m schi o Mom ka M lykh da ts da kora in Z - vera n

Stage 1: 7,7-dimethyl-11-(3-111-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo(| 16.3.1.1(5,8).0(9,14))tricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione (enantiomer 1) (Compound 5) and 17,1-dimethyl-11-(3-(11-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16 ,22- pentaazatetracyclo|16.3.1.1(5,8).0(9,14))gricose-1(21),9(14),10,12,18(22),19-hexane-15,17, 17-trione (enantiomer 2) (Compound 6)

oh oh oh oh oh oh oh uk | 4 M iv Dn | M m iv Kk r m m M.

Racemic 7,1-dimethyl-11-(3-(11-("trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22-pentaazatetracyclo| 16.3.1.1(5,8).0(9,14))gricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione (31 mg, 0.05119 mmol) was subjected to chiral purification by NCR using SpPigaIRak A5-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 2095 methanol/80 90 carbon dioxide at 10 ml/min, obtaining as the first eluted enantiomer of 7,7-dimethyl-11-(3-C1-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracycloyl16.3.1.1 (5,8).0(9,14)Ugricose-1(21),9(14),10,12,18(22),19-hexane-15,17,17-trione (enantiomer 1) (compound 5) (11.5 mg, 74 90); MO-

IER t/2 calc. 605.2032, found 606.2 (M--1)k; Retention time: 2.02 min (LC method E), and as the second eluted enantiomer 7,7-dimethyl-11-(3-(11-(trifluoromethyl)cyclopropyl|methoxy)-1H-pyrazol-1-yl) -17A6-thia-2,8,10,16,22-pentaazatetracycloyi16.3.1.1(5,8).0(9,14)Ugricose-1(21),9(14),10,12,18( 22),19-hexane-15,17,17-trione (enantiomer 2) (compound 6) (11.4 mg, 72 90); MO-

IER t/2 distr. 605.2032, found 606.2 (M--1) k; Retention time: 2.02 min (method RH E).

Example 110: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9 ,11-triazatetracyclo|18.3.1.05,10.011,15|tetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (enantiomer 1) (Compound 7) ii 12,12-dimethyl-8-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11-triazatetracyclo |18.3.1.05,10.011,15|tetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (enantiomer 2) (Compound 8)

OM5 x i and B i in sample 1 Nm 7 oh on sample 2

VosM -0--sh M | ro x , 0-Y M si on o Kk shi s

VosM

Yi Ba (Oh

V i y: m - M SI zer Z M | - our o - o--IM M M - eta trt

VosM

OO OO WE

X/Y x Z 5 M 7 M | schi u pomsa Jv 7 -- (c) -

Es

I am epapioteg 2 epapioteg 1

Stage 1: tert-butyl 2,2-dimethyl-5-I3-(3-sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate oo

KYA HM

ОоМ5 8 Z ho NM NM ---oo

VosM on Fr

3-Hydroxybenzenesulfonamide (510 mg, 2.945 mmol) and M,M-dimethylformamide (10.20 mL) were added to a 50 mL round-bottom flask. Potassium carbonate (1.425 g, 10.31 mmol) and tert-butyl-2,2-dimethyl-5-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.017 g, 3.033 mmol) were added to the mixture at room temperature and stirred at at room temperature for 3 h, then heated to 50 "C overnight. Cooled to room temperature and poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml), combined organic layers, washed with water (2 x 100 ml ), dried (sodium sulfate), filtered and concentrated. The brown residue was purified by chromatography on silica gel using a gradient from 100 90 hexanes to 100 95 ethyl acetate to give tert-butyl-2,2-dimethyl-5-IZ3 as a light orange oil -(3-sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate (770 mg, 6395). , 2H), 7.31 (5, 2H), 7.13 (a, U - 7.8 Hz, 1H), 4.02 (i,

In same 6.0 Gu, 2H), 3.85 - 3.67 (t, 1H), 1.88 (da, 9 - 11.6, 6.6 Hz, 2H), 1.79 - 1.61 (t, 4H), 1.51 (ad, y - 37.7, 5.8 Hz , 2H), 1.38 (5, 12H), 1.24 (5, ЗН). MO-IER t/ calc. 412.2032, found 413.2 (Mt) k; retention time: 1.81 min. (Method of RH E).

Stage 2: tert-butyl 5-I3-I3-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|Ifenoxy| propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate 8 and 5 M

NA and he | N

IF Shev -- 5-47 M Ts Iv x 0-47 - th

VosMm

VosMm

2-Chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (650 mg, 1.730 mmol) and carbonyldiimidazole (345 mg, 2.128 mmol). N,M-dimethylformamide (5.850 mL) was added, and the mixture was stirred at 40 °C under nitrogen for 1 hour. In a separate 100 mL flask, tert-butyl-2,2-dimethyl -5-N3-(3-sulfamoylphenoxy)propyl|pyrrolidine-1-carboxylate (750 mg, 1.818 mmol) under nitrogen in anhydrous M,M-dimethylformamide (5.850 mL).

Mann (77.0 mg, 1.925 mmol) (60 90 oil suspension) was added in portions and the mixture was stirred under a nitrogen atmosphere until gas evolution ceased. The vessel was covered with a lid and stirred at room temperature for 45 minutes. The two mixtures were combined and stirred at room temperature for 20 hours. It was heated to 55 "C for another 4 hours. Water and ice were added, and then concentrated hydrochloric acid was added dropwise until a white precipitate remained. Then

The mixture was washed with ethyl acetate and the combined organic layers were washed with brine, then washed 1:1 with saturated aqueous sodium bicarbonate/1 N. with sodium hydroxide (ZH), dried over sodium sulfate, filtered under vacuum and concentrated. The residue was then dissolved in 10 mL dichloromethane and purified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 65 95 ethyl acetate in hexane to give tert-butyl 5-(3-IZ-C2-chloro-6-) as a white solid (3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|phenoxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (450 mg, 34 95 ). 1N

NMR (400 MHz, DMSO-ab) 1H NMR (400 MHz, DMSO) 5 8.39 (y, Y - 2.9 Hz, 1H), 8.11 (a, Y - 8.3 Hz, 1H), 7.68 (9, Y - 8.4 Hz , 1H), 7.62 - 7.51 (t, 2H), 7.46 (a, U - 1.9 Hz, 1H), 7.30 (a, U - 6.9 Hz, 1H), 6.18 (a, 9 - 2.9 Hz, 1H), 4.48 - 4.25 (t, 2H), 4.06 (5, 2H), 3.74 (5, 1H), 2.08 (ai, 9 - 9.0, 5.1 Hz, 2H),

1.88 (5, 2H), 1.71 (da, U - 25.9, 15.0 Hz, 4H), 1.55 (y, U - 5.7 Hz, 2H), 1.36 (5, 12H), 1.23 (5, ЗН), 0.96 (aa , 9 - 7.7, 3.8 Hz, 2H), 0.88 (5, 2H). MO-IER t/: calc. 769.2524, found 770.5 (Ma); retention time: 2.11 min. (Method RK 5).

Stage 3: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11 -triazatetracyclo|18.3.1.05,10.011,15)htetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione

OO oo skh r Y M ikh z M ko. 2 | y 5-0 m s ---I o uk M M - : and Y

VosM

Tert-butyl 5-I3-IZ-Ce-chloro-6-I3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl) was combined in a 50 ml round-bottomed flask |sulfamoyl|phenoxy|propyl|-2,2-dimethylpyrrolidine-i-carboxylate (445 mg, 0.5777 mmol) dissolved in dichloromethane (2.225 mL), followed by the addition of hydrochloric acid (4M in dioxane) (1.589 mL, 4M , 6.355 mmol) and the mixture was stirred for 2 hours.

The material was then concentrated under reduced pressure to dryness to obtain a material that was dissolved in dimethylsulfoxide (9 mL) followed by the addition of excess potassium carbonate (1.0 g, 7.236 mmol). The vessel was capped and heated to 150 °C on a hot plate for 20 hours. Cesium fluoride (131.6 mg, 31.98 μL, 0.8666 mmol) was added and the reaction mixture was heated to 170 °C for an additional 4 hours. The reaction mixture was filtered and then purified by reverse-phase preparative chromatography using a C18 column (40-70 acetonitrile-water - 5 mM trifluoroacetic acid) to give 12,12-dimethyl-8-(3-12-( 11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9,11-triazatetracyclo|18.3.1.05,10.011,15|tetracose-1(24 ),5(10),6,8,20,22-hexane-2,2,4-trione (15.3 mg, 4 95). MO-IER t/72 calculated 633.22327, found 634.2 (Ma-1); Retention time: 1.83 min (Method RH E).

Stage 4: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11 -triazatetracyclo|18.3.1.05,10.011,15)htetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (enantiomer 1) (Compound 7) and 12 ,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11- triazatetracyclo| 18.3.1.05,10.011,15|tetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (enantiomer 2) (Compound 8) o Ku o B he in

Co., Ltd. spapisteg t"

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Abthia-3,9,11-triazatetracyclo |18.3.1.05,10.011,15)hetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (15.3 mg, 0.02414 mmol) was subjected chiral purification of NCRC using SpigaiRak AZ-N (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 18 95 methanol/82 9o carbon dioxide at a speed of 10 ml/min with obtaining as the first enantiomer eluted in the form of dirty white solid, 12,12-dimethyl-8-(3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Abthia-3,9,11-triazatetracyclo |18.3.1.05,10.011,15|tetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (enantiomer 1) (Compound 7) (3,4 mg, 44 to), MO-IER t/: distr. 633.22327, found 634.2 (M-n1) k;

Retention time: 1.84 min. 1 H-pyrazol-1-yl)-19-oxa-2Abthia-3,9,11-triazatetracyclo|18.3.1.05,10.011,15)tetracos-1(24),5(10),6,8,20, 22-hexane-2,2,4-trione (enantiomer 2) (compound 8) (3.4 mg, 44 95), MO-IER t/27 div. 633.22327, found 634.2 (M.-1) zhk; Retention time: 1.84 min (method RH E).

Example 111: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,19 ,24-pentaazatetracyclo|18.3.1.05,10.011,15|)tetracose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 16)

oh/y B o 7 A xx zier 1 pi | 5 hu on vier2

Vosm , i ryn M mod | and 0-7

And | kn Kk o g

VosM (in) B (in) 9/j

Mr. Mykh M - Mykh

AND; M si "ier3 and M M si viv

Es vs

VosM VosM o yy skh m y: shen

M o y M M M - N

Stage 1: tert-butyl 2,2-dimethyl-5-3-Kb-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate oo oo

MN ha r bony eh ti y:

VosM | Ts and M. 2 EE

E, /MN

VosM 5

Potassium carbonate (495 mg, 3.582 mmol), tert-butyl 5-(33-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (304 mg, 1.19 mmol), 6-fluoropyridine-2-sulfonamide were added to the vial. (208.9 mg, 1.186 mmol) and dimethylsulfoxide (3 mL). The reaction mixture was stirred at 80 "C overnight. The reaction was filtered and purified by HPLC (gradient 1 95-99 95 acetonitrile/water, modifier 0.1 95 hydrochloric acid) to give tert-butyl-2,2-dimethyl-5-I3 -(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (224.7 mg, 46 95) as a white foam. MO-IER t/2 calcd. 412.21442, found 413.8 ( M.-1) same, retention time: 0.94 min (Method RH B).

Stage 2: tert-butyl 5-I3-C6-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

NA and 5 on | Shchi) i, d- M | - ---»k 5-47 My si - Shchii z o- TM M si -

Mn k- - 7 MN total

VosMm

VosMm

2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)| pyrazol-1-yl| pyridine-3-carboxylic acid (204 mg, 0.5429 mmol), carbonyldiimidazole (93 mg, 0.5735 mmol) and tetrahydrofuran (3 mL). The reaction mixture was purged with nitrogen and placed in an oil bath preheated to 45 "C for 90 minutes. tert-butyl-2,2-dimethyl-5-3-(b-sulfamoyl-2-pyridyl)amino| propyl| pyrrolidine-1 was added -carboxylate (224 mg, 0.5430 mmol) followed by 1,8-diazabicyclo[5.4.0)undec-7-ene (250 μL, 1.672 mmol), and the reaction mixture was allowed to stir overnight at room temperature. the mixture was filtered and purified by HPLC (gradient 30-99 95 acetonitrile/water with 0.195 hydrochloric acid modifier), obtaining tert-butyl 5-IZ3-Cb-Ce-chloro-6-I3-(2-11-(trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (196.5 mg, 4795) as a white solid. IER t/2 calcd 769.2636, found 770.5 (M--1)k, retention time: 1.98 min (Method RH B).

Step 3: 2-chloro-M-((6-(3-(5,5-dimethylpyrrolidin-2-yl)propylamino|-2-pyridyl|sulfonyl|-6-(3-(2-P-"trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide

Her B HER KU 5-47 M si -y o dm MU si --

Kk d- MNoO 0 k - MN shko vas

VosM NM

Tert-butyl-5-I3-(C(6-Ce-chloro-6-I(3-(2-1P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl) was added to a round-bottomed flask |sulfamoyl|-2- pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (195 mg, 02532 mmol) and dichloromethane (5 mL).Hydrochloric acid (1.3 mL 4 M in dioxane, 5.200 mmol) and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction was evaporated to dryness. The reaction mixture was diluted with 3 M potassium carbonate to pH 10 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give /2-chloro-M-I(6-(3-(5,5- dimethylpyrrolidin-2-yl)/propylamino|-2-pyridyl|sulfonyl|/-6- IZ-(2-11- (trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (169 mg, 100 95). MO-IER t/72 calcd 669.2112, found 670.5 (M'-1)k; retention time: 0 ,78 min (method RH B).

Stage 4: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15|tetracose-1(23),5,7,9,20(24),21-hexane-

From 2,2,4-trione (Compound 16) ooo o r B

M - M M 0-0 MM M si o Den sa Iv - o MN - -k U ny

Potassium carbonate (175 mg, 1.266 mmol), cesium fluoride (58 mg, 0.3818 mmol) and a solution of 2-chloro-M-I(6-I3-(5,5-dimethylpyrrolidin-2-yl)propylamino) were added to the ampoule |-2-pyridyl|sulfonyl|- 6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (169 mg, 0.2522 mmol) in dimethylsulfoxide (3, 0 ml). The reaction mixture was heated in a sealed tube overnight at 150 °C. The reaction mixture was quenched with saline and extracted with ethyl acetate.

The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by chromatography on silica gel (0-50 95 ethyl acetate in a gradient of dichloromethane), obtaining 12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole-1 -yl)-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15|)tetracose-1(23),5,7,9,20(24),21-hexane -2,2,4-trione (compound 16) (93 mg, 5895) as a white solid. IN NMR (400 MHz, DMOO-av) b 12.75 (v, 1H), 8.23 (0, V - 2.7 Hz, 1H), 8.01 (a, -8.2 Hu, 1H), 7.58, 9 - 7.8 Hz, 1H) , 7.29 (5, 1H), 7.03 (y, U - 7.2 Hz, 2H), 6.63 (y, U - 8.4 Hz, 1H), 6.13 (y, -

2.1 Hz, 1H), 4.32 (Her, 9 - 7.1 Hz, 2H), 3.72 (5, 2H), 3.10 (5, 1H), 2.08 (I, 9 - 7.0 Hz, 2H), 1.86 (5, 2H) . MO-IER t/2 calc. 633.2345, found 634.2 (M--1) xx; retention time: 1.85 min. (Method of RH B).

Example 112: Preparation of 20,20,22-trimethyl-4-(3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9, 13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (compound 18) and 12,20,20-trimethyl -4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111, 14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 19) o o o Hm 95 OM xx on r vivri x v x M Vosm zier2 m | ru I HU -- Mo. | - and ro; And what on

M | I x M Eh U m? and | and | 5-47

VosM 9)

M ІІІ B and M X сх Mach

WHAT | and | N M 5-47 Mo A 5-47 Mo - -v3 5-7 shsh- ; 5-7 - ш тихичге ой гедиоивоте 5 nm c) оо Б р сх мах сх 7 хх | N M - y r; Meme M m em

And whether

Es

Stage 1: 2-chloro-M-((5-methyl-1H-pyrazol-4-yl)usulfonyl|)-6-I(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1- il|Ipyridine-3-carboxamide (c) O oo

KU ra te non z y I Mt

M | I that U et - | WE in cha 0-Y M si MN o-a«(y 5-7 - -

2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (100 mg, 0.2661 mmol), carbonyldiimidazole (48 mg, 0.30 mmol) and tetrahydrofuran (1 ml). The reaction mixture was stirred at 45 "C for 1 hour. Added

B-methyl-1H-pyrazole-4-sulfonamide (43 mg, 0.2668 mmol) and 1,8-diazabicyclo(|5.4.F)undec-7-ene (125 μL, 0.836 mmol) and the reaction mixture was allowed to stir. during the night at 45 "С.

The crude reaction mixture was filtered and purified by HPLC (gradient 10-99965 acetonitrile/water modified with 0.19% hydrochloric acid to give 2-chloro-M-((5-methyl-1H-pyrazol-4-yl)usulfonyl) |-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (80.0 mg, 58 95). MO-IER t/72 cal. 518, 0751, found 519.1 (M--T) Kk;

Holding time: 1.7 min. (Method of RH B).

Stage 2: tert-butyl 4-I3-I4-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-3Z- methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl-I(3-(4-((2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl) ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers)

Oh oh

M OM5 ek -Zh

M | in Y VosM i 2 - --e o- MTM M si

On

EC

(9)

M TO oh m x xx m y

M p - - - Vosm tikhiige oi gedioivotege

VosMm

In a round-bottomed flask containing 2-chloro-M-(5-methyl-1H-pyrazol-4-yl)sulfonyl/|-6-I(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy| To pyrazol-1-yl|pyridine-3-carboxamide (80 mg, 0.1542 mmol) was added N,M-dimethylformamide (2 mL), potassium carbonate (65 mg, 0.47 mmol) and tert-butyl-2,2 - dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (68 mg, 0.20 mmol) in M,M-dimethylformamide (2 ml). The reaction mixture was heated at 60 "C and stirred for 4 days.

The reaction mixture was filtered and purified by HPLC (gradient 30-99 96 acetonitrile/water with 0.1 95 hydrochloric acid modifier) to give tert-butyl 4-

Y3-I4-(2g-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-3-methylpyrazol-1-yl|Ipropyl |-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl 4-I3-I4-(2-chloro-6-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl| pyridine-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (49.9 mg, 43 95) as a white foam MS-IR t/2 calcd 757.2636, found 758.4 (Ma1)xc, retention time: 1.82 min (Method RH 5).

Stage 3: 2-chloro-M-I(1-3-(5,5-dimethylpyrrolidin-3-yl)/propyl|-3-methylpyrazol-4-yl|sulfonyl-6-I3-(2-P1-( trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide and 2-chloro-M-(1-

13-(5,5-dimethylpyrrolidin-3-yl)propyl|-5-methyl-pyrazol-4-yl|Isulfonyl-6-|3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1- il|Ipyridine-3-carboxamide (mixture of regioisomers)

I B I I

Ччх "7 вк чЩх m? dj-h y | И | Н M 5-4 Me and 5-4 Ma that --Щж - щ - - VosM tyzhige oggedioivoteg5

VosMm o B (F) oh xx M x hu m? db 5-47 M cho and 5-47 Mo o

НК тихиге ой гедиоизотег5

Tert-butyl-4-(3-I4-C(2-chloro-6-I3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl| sulfamoyl|-3-methylpyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl-4-(3-I(4-(e-chloro-6-|3- (2- P-«trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (49.9 mg, 0.0658 mmol), dioxane (1 mL), and hydrochloric acid (165 μL of 4 M in dioxane, 0.660 mmol).

The reaction was heated at 35 "C overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-M-/1-I3-(5,5-dimethylpyrrolidine-3- yl)propyl|-3-methylpyrazol-4-yl|sulfonyl-6-I(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide Chi 2-chloro- / M-(11-(3-(5,5-dimethylpyrrolidin-3-yl)/propyl|-5-methylpyrazol-4-yl| sulfonyl-b-I3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazole -1-yl|Ipyridine-3-carboxamide (mixture of regioisomers) (42 mg, 97 95) as a white solid MO-IER t/2 calcd 657.2112 found 658.4 (Ma1) xx; : 0.74 min (method RH B).

Stage 4: 20,20,22-trimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 18) and 12,20,20- trimethyl-4-(3-2-1P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14-pentaazatetracyclo|16.2.1.111,14.02 ,7 |docosa- 2,4,6,11(22),12-pentane-8,10,10-trione (Compound 19) b oo o oo

And x/Y hu M X hu m? where 5-47 M si and 5-47 Mi SI M --- 7 5 - NM tihiige og hedioizotegv

NM

(0) ra y M t sh M ik | N M s r; kt WE a

And I shko;

In a round-bottomed flask containing 2-chloro-N-(1-N3-(5,5-dimethylpyrrolidin-3-yl)propyl/|-3-methylpyrazol-4-yl|sulfonyl-6-N(3-( 2-I11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-

3-carboxamidyl /2-chloro-M-P1-(3-(5,5-dimethylpyrrolidin-3-yl)propyl|-5-methylpyrazol -(-4-yl|sulfonyl-6-I(3-(2 -11-(Trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (mixture of regioisomers) (42 mg, 0.06382 mmol) was added potassium carbonate (44 mg, 0.32 mmol), cesium fluoride ( 50 mg, 0.33 mmol), dimethyl sulfoxide (2 ml) and four molecular sieves Z A.

The reaction was heated at 150 C overnight. The reaction mixture was cooled to room temperature

From the temperature, it was filtered and purified by HPLC (gradient 10-99 95 acetonitrile/water with a modifier of 0.196 hydrochloric acid), obtaining as the first eluted isomer 20,20,22-trimethyl-4-(3-(2-P1-( "trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14-pentaazatetracycloi|16.2.1.111,14.02,7 |docosa-2,4,6, 11(22),12-pentane-8,10,10-trione (compound 18) (2.8 mg, 7 95) as an orange solid. IN NMR (400 MHz, dmeso-avb) b 12.39 (5, 1H), 8.18 (a, 9U - 2.8 Hu, 1H), 7.86 (5, 1H), 7.77 (a, U - 8.3 Hz, 1H), 6.90 (y, 9 -

8.2 Hz, 1H), 6.09 (y, 9U - 2.7 Gu, 1H), 4.43 - 4.34 (t, 1H), 4.30 (Y, U - 7.0 Hz, 2H), 4.08 - 3.96 (t, 1H), 2.06 ( d, U - 7.4 Hz, 6H), 1.95 - 1.69 (t, 4H), 1.55 (5, ЗН), 1.47 (v, ЗН), 1.40 - 1.08 (t, AN), 0.96 (19, - 4.9, 4.4 , 3.1 Hz, 2H), 0.90 - 0.85 (t, 2H), MO-IER t/2 calc. 621.2345, found 622.6 (M.-1) k;

Holding time: 1.48 min. (Method of RH B) apa az She 5esopa isoteg io eiYshe, 12,20,20-iiteiNu!-4-(3- 12-P1-ChitPiogoteiNui)susiorgoruTseshyohu)-1 H-ruga?201-1-il)-10X6- thia-1,3,9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|dosose-2,4,6,11(22),12-repiacepe-8,10,10-trione (Compound 19) (3.7 mg, 9 95) az ap ogapde 5oiid; YAN NMR (400 MHz, DMSO-a6) b 12.18 (5, 1H), 8.41 (5, 1H), 8.18 (a, 9 - 2.8 Hu, 1H), 7.75 (a, U - 8.2 Hu, 1H), 6.89 (a, U - 68.2 Hz, 1H), 6.10 (a, U - 2.8 Hz, 1H), 4.31 (i, U t 7.0 Gu, 2H), 4.22 (y, U - 13.6, 3.68 Hz, 1H), 3.97 (i, y - 12.4 Hu, 1H), 2.40 (5, ЗН), 2.20 (5, 1H), 2.07 (9 7.1 Hu, 4H), 2.02 - 1.68 (t, 4H), 1.51 (a, U - 13.0 Hz, 6H), 1.38 (I, )U - 12.3 Hz, 1H), 1.03 (5, 1H), 0.96 (9, U - 5.0, 4.5, 3.2 Hz, 2H), 0.93 - 0.84 (t, 2H), MO-IER t/2 calc. 621.2345, found 622.4 (M-AT) flat; Holding time: 1.54 min. (Method of RH B).

Example 113: Preparation of 7,7-dimethyl-11-(3-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10, 16,22-pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1(21),9511,13,18(22),19-hexane-15,17,17-trione (Compound 20) o o, /o Oh

M I ziver1 M ro M ziver2

M -- k M iy - I - -2-kzh - -- - - --2e i -k M si o / M M SI ek Mn 5 - MN - Eighth

Yi Mish

Se V zisyr 5-47 We si -ya vierz mm | ME m A i - izlshny i 5 shi6- MN pl code all oy

Stage 1: tert-butyl 4-(2-C6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate e) o (HER U m - 4 рр M 4 She tm M si 0-0 M si ven MN Kk o MN vs ES - -

2-Chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl pyridine-3-carboxylic acid (615 mg, 1.64 mmol), carbonyldiimidazole (279 mg, 1 .72 mmol) and tetrahydrofuran (3 ml). The reaction mixture was stirred at 45 "C for 2 hours. Tert-butyl-2,2-dimethyl-4-(2-(b-sulfamoyl-2-pyridyl)amino|ethyl) was added |pyrrolidine-1-carboxylate (654 mg, 1.641 mmol) followed by 1,8-diazabicyclo/5.4.Fundec-7-ene (750 μL, 5.02 mmol), and the reaction mixture was allowed to stir at 45 °C overnight . The reaction was quenched with 1N citric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by chromatography on silica gel (10 95 -100 95 ethyl acetate in hexane gradient) gives tert--butyl-4 -(2-(6-Ce-chloro-6-I(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-

Zo pyridylamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (830 mg, 67 95) as a white solid. MO-IER t/2 calc. 755.248, found 756.5 (М--1)хк; retention time: 1.8 min. (Way

РХ 5).

Stage 2: 2-chloro-M-(6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl|)-6-(3-(2-

N-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide

HER KY her KY skh m skh z m skh

M still more what what o-- M M si 0-4 k- o mno 77 k- o Mn vs ts

In a round-bottomed flask containing tert-butyl-4-(2-I((6-(e2g-chloro-6-I3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin- To 3-carbonyl|sulfamoyl|-2-pyridylyamino|ethyl|-2,2-dimethylpyrrolidine-i-carboxylate (830 mg, 1.098 mmol) was added dichloromethane (2 mL) and hydrochloric acid (2.75 mL of 4 M in dioxane, 11 .00 mmol) After 40 minutes, the reaction was quenched with saturated sodium bicarbonate and extracted twice with ethyl acetate.

The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 2-chloro-M-I(6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl)sulfonyl)-6 -I(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide) (715 mg, 99 95) as a white solid. 1H NMR (400 MHz, DMSO- ab) b 8.35 (j, y - 2.8 Hz, 1H), 8.11 (a, U - 8.3 Hz, 1H), 7.62 (9.9 - 8.2 Hz, 1H), 7.44 (aa, U - 8.3, 7.3 Hz, 1H), 6.98 (ai, 9 - 7.2, 0.8 Hz, 1H), 6.84 (I, - 5.8 Hz, 1H), 6.47 (aa, U - 8.3, 0.8 Gu, 1H), 6.12 (a, U - 2.8 Hz , 1H), 4.33 (I, U - 7.0 Hz, 2H), 3.81 - 3.69 (t, 1H), 3.17 (dd, u - 12.3, 5.68 Hz, 1H), 3.09 - 2.97 (t, 1H), 2.39 r, U - 8.0 Hz, 1H), 2.08 1.9 - 7.1

Hz, 2H), 1.95 (da, U - 12.8, 7.7 Hz, 1H), 1.62 (ar, U - 19.9, 6.4 Hz, 2H), 1.35 (aa, U - 12.6, 10.2 Hz, 1H), 1.26 (y , 7 - 32.0 Hz, 6H), 1.01 - 0.84 (t, 4H). MO-IER t/7 calc. 655.19556, found 656.6 (MA) k; retention time: 0.78 min. (Method of RH B).

Stage 3: 7,7-dimethyl-11-(3-12-11-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo |16.3.1.15,8.09,14Hygricose-1(21),9,11,13,18(22),19-hexane-15,17,17-trione (Compound 20)

Oo oo

КИ о шх m з КБ

N | s r s

M. ra Mykh | Y sh- Mn o y M M M - - MN nm

Potassium carbonate (263 mg, 1.90 mmol), cesium fluoride (133 mg, 0.876 mmol), four molecular sieves Z A, 2-chloro-M-((6-(2-(5,5- dimethylpyrrolidin-3-yl)ethylamine1|-2-pyridyl|sulfonyl|-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (250 mg, 0.381 mmol ) and dimethylsulfoxide (7 ml). The reaction mixture was closed and placed in an oil bath preheated to 155"C overnight. The reaction was diluted with ethyl acetate and quenched with 1N citric acid, and then with brine. The reaction mixture was extracted twice with ethyl acetate, dried over sodium sulfate, filtered and evaporated.

The crude reaction mixture is purified by silica gel chromatography (095-100 95 ethyl acetate in hexane gradient) to provide 7,7-dimethyl-11-(3-(2-11-

Zo (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-1 7A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15,8.09,14|tricose-1(21) ,9,11,13,18 (22),19-hexane-15,17,17-trione (Compound 20) (101 mg, 4395). MO-IER t/2 calc. 619.2189, found 620.2 (МА1)ж; Holding time: 2.07 min. (Method of RH B).

Example 114: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2,bthia-3,9,11,18 ,22-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (hydrochloride salt) (Compound 23 )

(c) about B m M M Y podonya | From Wavery On | 7 uv; Zier2

II z " y -- o -4 i o ul MU oyi

M

/

Vos

Oo oo

Kk xx 7 Heh

Кк ш-- МН 5-47 М М

EC -- Plural

My

Stage 1: tert-butyl 2,2-dimethyl-4-3-K2-sulfamoyl-4-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate oo

KFFya I o shchi RE;

VosM o Y M NA | - nm | and -zZ-- me

PO t - (c)

Mn, Mn

M

/

Vos

4-Aminopyridine-2-sulfonamide (310 mg, 1.79 mmol) and cesium carbonate (900 mg, 2.76 mmol). The reaction mixture was stirred at 70 "C for 4 h. The reaction mixture was cooled to room temperature and poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml), the organic layers were combined, washed with brine, dried (sodium sulfate) , filtered and concentrated, obtaining tert-butyl 2,2-dimethyl-4-I3-(2-sulfamoyl-4-pyridyl)amino|Ipropyl|pyrrolidine-i-carboxylate, which was used directly in the next stage (369 mg, quantity ). IN NMR (400 MHz, DMOO-ab) 5 8.32 (riv, 2H), 8.12 (ad, 9 - 6.6, 1.6 Gu, 1H), 7.24 (ai, U - 6.3, 2.4 Hz, 1H), 6.87 ( ai, U - 6.7, 2.0 Hz, 1H), 3.50 (d, y - 9.0 Hz, 2H), 3.40 - 3.28 (t, 1H), 2.96 (p, y - 7.0, 6.4 Hz, 2H), 2.83 - 2.68 (t, 1H), 2.07 - 1.96 (t, 1H), 1.89 - 1.74 (t, 2H), 1.45 - 1.26 (t, 14H), 1.23 (5, ZN). MO-IER n/2 calc. 412, 21442, found 413.5 (MT) gk, retention time: 0.52 min (Method RH A).

Stage 2: tert-butyl 4-I3-C2-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-4-pyridylamino |propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

WE are about Я B

В M сх M Mo что го" cache - M ru -0--ш o u m si x s-m M si - a. --e sh-i z ws

M M weight

A solution of 2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxylic acid (300 mg, 0.798 mmol) and carbonyldiimidazole (130 mg, 0.802 mmol) in tetrahydrofuran (5 mL) was stirred for 45 min. Then, tert-butyl-2,2-dimethyl-4-III-(2-sulfamoyl-4-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (330 mg, 0.800 mmol ) and 1,8-diazabicyclo(/5.4.Fundec-7-ene (150 μl, 1.00 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed saline solution, dried over sodium sulfate, filtered and evaporated, obtaining an oily material, which was purified by reversed-phase HPLC-MS using a column I ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (art. : 00С-4252-00-АХ), and a double gradient from 195 to 9995 of mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - a cetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "C) with obtaining the desired product tert-butyl 4-I3-(2-(2-chloro-6-I3-(2 -P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|- 4-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (23 mg, 4 95) in the form off-white sticky material. 1H NMR (400 MHz, DMSOO-ab) b 8.40 (a, 9 - 2.8 Hu, 1H), 8.15 (a, U - 5.6 Hz, 1H), 7.96 (a, 9 - 8.3 Hu, 1), 7.66 (a , U - 8.3 Hz, 1), 7.00 (a, U - 2.2 Gu, 1H), 6.80 (5, 2H), 6.69 (ai, U - 5.7, 2.2 Hz, 1H), 6.18 (a, U - 2.8 Hz , 1H), 4.34 (Y, U - 7.1 Hz, 2H), 3.81 - 3.71 (t, 1H), 3.54 (d, U - 8.3

Gu, 1H), 2.77 (ad, U - 10.0 Hz, 1H), 2.18 - 2.02 (t, 4H), 1.90 - 1.77 (t, 1H), 1.74 - 1.65 (t, 1H), 1.43 - 1.32 (t, 14H), 1.22 (5, ЗН), 1.01 - 0.94 (t, 2H), 0.91 - 0.87 (t, 2H). MO-IER t/: calc. 769.2636, found 770.7 (M--1) zhk; Retention time: 0.87 min (RC method A).

Stage 3: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,22- pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (hydrogen chloride salt) (Compound 23)

Oo oo

WE

This is what I am and Io /ofi | p

Kk -x MN 5-47 M M and zo d- MN

M

/

Vos

Tert-butyl 4-I3-C2-C2-chloro-6-I3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|4-pyridylamino|propyl |-2,2-dimethylpyrrolidine-1-carboxylate (20 mg, 0.026 mmol) was dissolved in dioxane (1.0 mL) and hydrochloric acid (4M in dioxane) (250 μl 4 M, 1.0 mmol) was added to the mixture. and the resulting mixture was stirred at room temperature

From the temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure, re-dissolved in ethyl acetate, then aqueous 2 M sodium carbonate (5 ml), pH - 10, was added.

The organic layer was extracted with ethyl acetate (2 x 10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, obtaining material that was combined with potassium carbonate (20 mg, 0.14 mmol), fluoride cesium (10 mg, 0.066 mmol) and dimethyl sulfoxide (2.0 mL) in a vial. The vial was purged with nitrogen, closed, heated to 150 °C and stirred for 16 h. It was cooled to room temperature, and the reaction mixture was filtered through a UUpantap disc filter (Rigaadivs 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using column I ipa C18 (2) (75 x 30 mm, particle size 5 μm), which is sold by Rpepotepeh (art.: 00С-4252-00-АХ), and a double gradient from 50 95 to 99 95 of mobile phase B for 15.0 min (mobile phase A - water (5

MM hydrochloric acid), mobile phase B - acetonitrile. The flow rate is 50 ml/min, the injection volume is 950 μl, and the column temperature is 25 "С) to obtain 12,12-dimethyl-8-(3-(2-(/1- (trifluoromethyl)cyclopropyl|ethoxy) )-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,22- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(23),5(10), 6,68,19,21-hexane-2,2,4-trione (hydrochloride salt) (compound 23) (1.6 mg, 9 95) as a white solid. MO-IER t/: calc. 633, 2345, found 634.6 (M--1) k Retention time: 2.15 min (Method RH B).

Example 115: Preparation of 6b,b-dimethyl-10-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-16Abthia-2,7,9,15,21 -pentaazatetracyclo|15.3.1.14,7.08,13|docose-1(20),8,10,12,17 (21),18-hexane-14,16,16-trione (Compound 17)

VyMm Zier1 Osm ier2 Osm | y: er z -- -- - y DA ov, ZZ2Z-30- on on MN. M AH Ltd

M (in) 7 xx

M 2 - - -- k 5-47 M si

Mn p

VosM

ОО оо чр ч Ty B no Zmy ХХ Zhe -U M si - M | - y y ra (o) zier5 -

Gee! and МММ - МН and ЖК ко код шко;

VosM

Stage 1: tert-butyl-4-(hydroxymethyl)-2,2-dimethylpyrrolidine-1-carboxylate

(1-benzyl-5,5-dimethylpyrrolidin-3-yl)methanol (1 g, 4.56 mmol) was dissolved in EUN (40 ml), 20 95 RY(OH)2 on charcoal was added (400 mg) and the reaction mixture was stirred in a hydrogen atmosphere at 20 C for 24 hours. The catalyst was filtered through celite. The precipitate on the filter was washed with ethyl acetate and the filtrate was concentrated. The crude intermediate was dissolved in tetrahydrofuran/water (50 mL/50 mL) and potassium carbonate (3.1 g, 22.8 mmol) was added, followed by Bos20O (1.22 g, 4.56 mmol) at 0°C. . The reaction mixture was allowed to warm to 207 for 16 hours, then poured into water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Pure tert-butyl-4-(hydroxymethyl )-2,2-dimethylpyrrolidine-1-carboxylate (1.04 g, quantity)

It was obtained as a colorless oil after purification on silica gel (eluted with 30 95 ethyl acetate in heptanes). IN NMR (300 MHz, SOSIZ): a 3.6 (t, 4H); 3.1 (t, 1H); 2.4 (t, 1H); 1.9 (t, 1H); 1.4 (t, 15Н).

Stage 2: tert-butyl-4-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate

VosmM VosM -- yes he is MN,

M5CIII (0.57 mL, 7.3 mmol) was slowly added to a solution of tert-butyl-4-(hydroxymethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.4 g, 6.1 mmol) and OIREA (1 .6 ml, 9.15 mmol) in dichloromethane (30 ml) at 0 "C. The reaction mixture was stirred for 1 h, water was added, the layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude mesylate was dissolved in M,M-dimethylformamide (20 mL), Mam3 (600 mg, 9.15 mmol) was added, and the reaction mixture was stirred in a closed vessel at 100 "C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with saline, dried over sodium sulfate, filtered and concentrated.

The crude azide was dissolved in a mixture of tetrahydrofuran/water (18/2 mL), PPRIZ (2.4 g, 9.15 mmol) was added, and the reaction mixture was stirred at 50 "C for 3 hours. The reaction mixture was cooled, carefully acidified to pH 3 by with 4N aqueous hydrochloric acid and washed rapidly with ethyl acetate (2 x 20 mL). The aqueous layer was basified to pH 10 and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give tert -butyl-4-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (600 mg, 4395) as a yellow oil after purification on silica gel (eluted with 5 90 methanol in dichloromethane).IN NMR (300 MHz, SOSIS): and 3.7 (t, 1H); 3.0 (t, 1H); 2.7 (t, 2H); 2.2 (t, 1H); 1.9 (t, 1H); 1.4 (t, 15H).

Stage 3: tert-butyl 2,2-dimethyl-4-((6b-sulfamoyl-2-pyridyl)amino|methyl|pyrrolidine-1-carboxylate oo

M

And many 53

MN, here I am / oh

MN

Ki

In a 20 mL vial, b-fluoropyridine-2-sulfonamide (340 mg, 1.9 mmol) was combined in dimethyl sulfoxide (4.0 mL), then potassium carbonate (1.3 g, 9.4 mmol) and tert-butyl 4-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (460 mg, 2.0 mmol). The vessel was covered with a lid and heated to 100 "C on a hot plate for 16 hours. The reaction mixture was cooled to room temperature, then filtered, diluted with ethyl acetate and washed with 1 M citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 80 95 ethyl acetate in hexane, to give tert-butyl-2,2-dimethyl-4-|(b-sulfamoyl-2-pyridyl)amino| methyl|pyrrolidine-1-carboxylate (222 mg, 30 95) as a white solid. 1H NMR (400 MHz, DMSO-ab) b 7.53 (aa, U - 8.4, 7.3 Hz, 1H), 7.10 (5, 2H ), 7.06 (a, U - 5.5 Hz, 1H), 6.97 (y, U - 6.9 Hz, 1H), 6.64 (a, U - 8.1 Hz, 1H), 3.65 - 3.54 (t, 1H), 3.17 (a , U - 5.2 Hz, 2H), 2.95 (Her,

In the same 101 Hu, 1H), 2.47 - 2.35 (t, 1H), 2.00 - 1.86 (t, 1H), 1.55 (ai, 9 - 32.7, 12.1 Hz, 1H), 1.42 - 1.36 (t, 12H), 1.25 (5, ZN). MO-IER t/2 calc. 384.18314, found 385.2 (M--1)w; retention time: 1.46 min. (Method of RH E).

Stage 4: tert-butyl 4-((6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino) |methyl/|-2,2-dimethyl-pyrrolidine-1-carboxylate o o, /e

B 9 so xx 7 y | N iv xx on M. - M cy s M si - dsch - Mn

I

eighth

VocmM 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (202 mg, 0.538 mmol) and carbonyl diimidazole (87.5 mg, 0.540 mmol) were combined in tetrahydrofuran (3.0 ml) and stirred for 2 h at 45 "C. Then tert-butyl-2,2-dimethyl-4-((6b-sulfamoyl-2-pyridyl)amino) was added. methyl|pyrrolidine-1-carboxylate (207 mg, 0.538 mmol) followed by 1,8-diazabicyclo/5.4.0)undec-7-ene (175 μL, 1.17 mmol), and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid, then brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 7095 ethyl acetate in hexane to obtain // tert-butyl-4-(C(6-C2-chloro-6-I3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1-

yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|methyl/|-2,2-dimethylpyrrolidine-1-carboxylate (234 mg, 59 9v5) as a light yellow solid. 1H NMR (400 MHz, DMSO-ab) b 12.79 (5, 1H), 8.40 (t, 1H), 8.09 (a, U - 8.4 Hz, 1H), 7.70 (1, 9 - 7.0 Hz, 1H), 7.63 (t, 1H), 7.28 (5, 1H), 7.19 (a,

U - 7.2 Hz, 1H), 6.77 (y, 9 - 8.6 Hz, 1H), 6.19 (ad, U - 4.4, 2.9 Hz, 1H), 4.34 (i, 9 - 7.1 Hz, 2H), 3.55 (t, 1H), 3.26 (t, 2H), 2.91 (Yii, U - 10.4 Hu, 1H), 2.41 (t, 1H), 2.09 (Yii, U 2 7.1 Hu, ZN), 1.86 (t, 1H), 1.50 ( t, 1H), 1.35 (I, U - 13.2 Hu, 12H), 1.18 (5, ЗН), 0.95 (t, 2H), 0.89 (5, 2H). MO-IER t/2 calc. 141.2323, found 742.2 (M--1) k; retention time: 2.25 min. (Method of RH E).

Stage 5: 6,6b-dimethyl-10-(3-(2-1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-166bthia-2,7,9,15,21-pentaazatetracyclo |15.3.1.14,7.08,13|docose-1(20),68,10,12,17(21),18-hexane-14,16,16-trione (Compound 17) o oo h Shk h o B n | и и Эх 5-47 be to zhk | MU m y - - w 0-7 - ter

Es

Geo

tert-butyl 4-((6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-

3-Carbonyl|Isulfamoyl|-2-pyridylyamino|methyl|-2,2-dimethylpyrrolidine-i-carboxylate (234 mg, 0.315 mmol) was dissolved in dichloromethane (5.0 mL) and hydrochloric acid (3.0 mL) was added to the mixture 4 M in dioxane, 12.0 mmol) and stirred at room temperature for 2 hours.

The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then aqueous 2M sodium carbonate (2 ml), pH - 10, was added. The organic layer was extracted with ethyl acetate (2 x 5 ml), washed with saline, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. This material was combined with potassium carbonate (220 mg, 1.59 mmol), cesium fluoride (72.0 mg, 0.474 mmol), Z A molecular sieves, and dimethyl sulfoxide (7.0 mL) in a nitrogen-purged, capped vial. , heated to 155 "C. and stirred for 16 hours. It was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then was purified by chromatography on silica gel using a gradient from 100 95 hexanes to 8095 ethyl acetate in hexane to obtain 6,6b-dimethyl-10-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole-1- yl)-16A6-thia-2,7,9,15,21- pentaazatetracyclo!|15.3.1.14,7.08,13|docose-1(20),8,10,12,17(21),18-hexane- 14,16,16-trione (compound 17) (111 mg, 57 95) as a white solid, TN NMR (400 MHz, DMSO-ab) b

Zo 12.52 (5, 1H), 8.19 (a, 9U - 2.7 Hz, 1H), 7.67 - 7.50 (t, 2H), 7.47 (a, y - 8.1 Gu, 1n), 7.16 (a, 7.2

Hz, 1H), 6.82 (a, U - 8.1 Hz, 1H), 6.73 (y, U - 8.5 Hz, 1H), 6.09 (y, U - 2.7 Hz, 1H), 4.52, 9 - 9.68 Hz, 1H) , 4.30 (1, 7 - 7.0 Hz, 2H), 3.54 - 3.42 (t, 1H), 3.27 - 3.16 (t, 1H), 3.02 (I, 9 - 8.7 Hz, 1H), 2.32 (a,

U - 12.3, 5.7 Hz, 1H), 2.07 (yes, U - 8.7, 5.4 Hz, 2H), 1.97 (49, U - 11.4, 5.68 Hz, 1H), 1.68 (5, ЗН), 1.64 (a, U - 12.2 Hz, 1H), 1.45 (5, ZN), 0.95 (I, U - 5.68 Hz, 2H), 0.87 (5, 2H). MO-IER ip/2 calc. 605.2032, found 606.4 (M--1) same; retention time: 2.02 min. (Method of RH E).

Example 116: Preparation of 6b,b-dimethyl-10-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-16Abthia-2,7,9,15,21 -pentaazatetracyclo|15.3.1.14,7.08,13|docosa- 1(20),8,10,12,17(21),18-hexane-14,16,16-trione (enantiomer 1) (Compound 24) and 6 ,6-dimethyl-10-(3-12-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-16Abthia-2,7,9,15,21- pentaazatetracycloi|15.3.1.14,7.08,13|docosa-1(20),8 ,10,12,17(21),18-hexane-14,16,16-trione (enantiomer 2) (Compound 25) 2 B o i o B

Stage 1: 6,6b-dimethyl-10-(3-(2-1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-166bthia-2,7,9,15,21-pentaazatetracyclo |15.3.1.14,7.08,13|docose-1(20),68,10,12,17(21),18-hexane-14,16,16-trione (enantiomer 1) (Compound 24) and 6,6b -dimethyl-10-(3-12-11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-16Abthia-2,7,9,15,21- pentaazatetracyclo|15.3.1.14,7.08, 13|docose-1(20),8,10,12,17(21),18-hexane-14,16,16-trione (enantiomer 2) (Compound 25)

OH Her Reverend (Shk

Racemic 6,6b-dimethyl-10-(3-(2-1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-16X6-thia-2,7,9,15,21-pentaazatetracyclo |15.3.1.14,7.08,13|docose-1(20),8,10,12,17(21),18-hexane-14,16,16-trione (131 mg) was subjected to chiral NKR chromatography using SpigaIRak AB-H (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 15 95 acetonitrile:methanol (90:10)/85 90 carbon dioxide at 10 ml/min, which gives 6b as the first eluted enantiomer, 6-dimethyl-10-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-16X6-thia-2,71,9,15,21-pentaazatetracyclo|15.3.1.14 ,7.08,13|docose-1(20),8,10,12,17(21),18-hexane-14,16,16-trione (enantiomer 1) (compound 24) (29.04 mg, 69 95 ) in the form of a not quite white solid; 1N

NMR (400 MHz, DMSO-ab) b 12.52 (5, 1H), 8.19 (9, U - 2.7 Hu, 1H), 7.61 (aa, U - 10.5, 5.2 Hz, 2H), 7.47 (au 81 Hu, 1H ), 7.16 (a, U - 7.2 Hu, 1H), 6.82 (a, 9 - 8.1 Hu, 1H), 6.73 (a, U - 8.5 Hz, 1H), 6.09 (a, 9 - 2.7 Hz, 1H), 4.51 (1, U -10.0 Hz, 1H), 4.30 (I, U - 7.0 Hz, 2H), 3.58 - 3.38 (t, 1H), 3.22 (0.9 - 5.6 Hz, 1H), 3.09 - 2.95 (t , 1H), 2.40 - 2.20 (t, 1H), 2.07 (I, 9 - 7.0 Hz, 2H), 1.97 (ai, U 2 12.2, 6.2

Gu, 1H), 1.74 - 1.60 (t, 4H), 1.45 (5, ЗН), 0.95 (I, U - 5.7 Hz, 2H), 0.89 (a, U - 11.5 Hz, 2H), MO-IER t/ 7 calculations 605.2032, 606.2 (Ma-1) found; Retention time: 2.03 min. )-16A6-thia-2,7,9,15,21-pentaazatetracyclo|15.3.1.14,7.08,13|docosa- 1(20),8,10,12,17(21),18-hexane-14, 16,16-trione (enantiomer 2) (compound 25) (28.84 mg, 68 95) as an off-white solid; TN NMR (400 MHz, dimethyl sulfoxide-ab) b 12.52 (5, 1H), 8.19 (a, U - 2.7 Hu, 1H), 7.61 (aa, U - 10.3, 5.4 Hz, 2H), 7.47 (a, U - 8.1 Hz, 1H), 7.16 (a, - 7.2

Hz, 1H), 6.82 (y, 9U - 8.1 Hz, 1H), 6.73 (y, U - 8.4 Hz, 1H), 6.09 (y, 9 - 2.7 Hz, 1H), 4.51 (y, U - 9.9 Hz, 1H), 4.30 (i, U - 7.0 Hz, 2H), 3.58 - 3.41 (t, 1H), 3.22 (aa, U - 12.0, 5.7 Hz, 1H), 3.02 (I, U - 68.6 Gu, 1H), 2.31 (yes, 9 - 15.2, 6.3 Hz, 1H), 2.07 (1, 9. - 7.0 Hz, 2H), 1.97 (yes, U - 12.1, 6.3 Hz, 1H), 1.71 - 1.59 (t, 4H), 1.45 (5, ZN), 0.95 (I, 9 - 5.7 Hz, 2H), 0.89 (y, U - 11.5 Hz, 2H), MO-IER t/2 calc. 605.2032, found 606.2 (M'-1) t; Holding time: 2.03 min. (Method of RH E).

Example 117: Preparation of 7,7-dimethyl-11-(3-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10, 16,22-pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1(21),9511,13,18(22),19-hexane-15,17,17-trione (enantiomer 1) (Compound 26) and 7,7-dimethyl-1 1-(3-12-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15,8.09,14|tricose-1(21) ,9,11,13,18(22),19-hexane-15,17,17-trione (enantiomer 2) (Compound 27) and YII Ba Y 5

Stage 1: 7,7-dimethyl-11-(3-12-11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo |16.3.1.15,8.09,14Hygricose-1(21),9,11,13,18(22),19-hexane-15,17,17-trione (enantiomer 1) (Compound 26) and 7,1-dimethyl -11-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-1 7A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15, 8.09,14)|tricose-1(21),9,11,13,18(22),19-hexane-15,17,17-trione (enantiomer 2) (Compound 27)

TO TYA and Oh

Racemic 17,7-dimethyl-11-(3-2-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22- pentaazatetracyclo/16.3.1.15,8.09,14)|gricose-1(21),9,11,13,18(22),19-hexane-15,17,17-trione (85 mg, 0.1372 mmol) was subjected to effect of chiral NKR chromatography using SpigaIRak A5B-N (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 20 95 methanol (without modifier))/80 95 carbon dioxide at 10 ml/min with obtaining as of the first eluted enantiomer 7,7-dimethyl-1-(3-12-1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17Ab6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.15,8.09,14|tricose-1(21),9511,13,18(22),19-hexane-15,17,17-trione (enantiomer 1) (Compound 26) (241 mg, 28 95); MO-IER t/72 resolution 619.2189, found 620.2 (M. 1)g; Retention time: 2.07 min (RCH B method) and as the second eluted enantiomer 7,7-dimethyl- 11-(3-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17Ab6-thia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15,8.09, 14 | leotard z- 1(21),9511,13,18(22),19-hexane-15,17,17-trione (enantiomer 2) (compound 27) (26 mg, 31 95); MO-IER t/2 distr. 619.2189, found 620.2 (M. 1); Retention time: 2.06 min (method RH B).

Example 118: Preparation of 4-chloro-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2,4,6,11(22),12 -pentane-8,10,10-trione (Compound A) and 4-chloro-21,21-dimethyl-10Xbthia-1,3,9,14,15-pentaazatetracyclo!17.2.1.02,7.011,15|docosa- 2 ,4,6,11,13-pentane-8,10,10-trione (compound B) (9)

M HER M VosM HER seed? 7 oNndt HU vivri te S x submitted R, (o M (o 9) M (9) Kya y: "7 хх ех m 2nd n

S". sg re, si M (o SI M SI 7 p

Vos

Zier Z | Vier 4 o 54 o Ka c x M x 5 M x

Y si M od si M plo

Stage 1: 2,6-dichloro-M-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide o o o o o o o

WE HM y: he Z same y

TO US

2,6-dichloropyridine-3-carboxylic acid (1 g, 5.208 mmol) and carbonyldiimidazole (1.690 g, 10.42 mmol) in M,M- dimethylformamide (10.00 ml) was stirred at 50 "C for 1 hour.

A suspension of sodium hydride (312.5 mg, 7.812 mmol) in M,M-dimethylformamide was added to a solution of 1H-pyrazole-5-sulfonyl chloride (194.5 mg, 1.16 mmol, 1.5 equiv) in M,M-dimethylformamide and stirred for 30 min at room temperature in a separate flask. The two mixtures were combined and stirred at room temperature for 1 hour. The reaction mixture was poured onto ice and acidified to pH 2 by adding aqueous 4 M hydrochloric acid.

The resulting mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered, and volatile substances were removed by rotary evaporation. The crude material was purified by chromatography on silica gel, eluting with 1095 methanol in dichloromethane, to give 2,6b-dichloro-M-(1H-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide (1.341 g, 68 Vol).

MO-ER t/2 calc. 319.95377, found 321.0 (M--1)k; retention time: 0.34 min. (Method of RH A).

Stage 2: tert-butyl 4-I3-IZ3-K2,6-dichloropyridine-3-carbonyl)sulfamoyl|pyrazol-1-yl|propyl|/- 2,2-dimethyl-pyrrolidine-1-carboxylate o o o o Y M Y M

M eight her z t their n

2,6-Dichloro- M-(IN-pyrazol-3-ylsulfonyl)pyridine-3-carboxamide (300 mg, 0.934 mmol), then cesium carbonate (875 mg, 2.69 mmol), and the reaction mixture was stirred at 60 "C for 16 hours. the mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with water (2 x 100 mL), dried (sodium sulfate), filtered, and concentrated. The resulting brown the residue was purified by silica gel column chromatography using a shallow gradient from 100 95 hexanes to 100 o ethyl acetate with tert-butyl-4-(3-III--(2,6-dichloropyridine-3-carbonyl)usulfamoyl) as the first elution regioisomer |pyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (327 mg, 65 95) as a white solid. 1H NMR (400

MgGu, DMSOO-ab) b 7.92 (a, U - 8.0 Hz, 1H), 7.70 (a, 9 - 2.2 Hz, 1H), 7.51 - 7.46 (t, 1H), 6.48 (j, 9 - 2.3 Hz, 1H ), 4.14 - 4.05 (t, 2H), 3.53 (Her, U - 14.7, 10.3 Gu, 1H), 2.78 - 2.67 (t, 1H), 2.08 (ad, 9 - 11.7, 5.9, 5.3 Hz, 1H), 1.39 (5, 4H), 1.34 (d, U - 11.5, 8.4 Hz, 12H), 1.22 (5, ZN), MO-IER t/: cal. 559.1423, found 560.5 (М--1)-4; Holding time: 0.71 min. (Method of RH A) apa ah She 5esopa hedioizoteg" 10 yeishe, yep-bshiiu! 4-I3-(5-K(2,6-dispiogorugidipe-3-sagropu)zctatouPruga2o1-1-yl|rgorui|- 2,2- Dimethyl-rutoidipe-1-sagrohuyl (126 mg, 25 Fo) az a mizoi5 soogies55 oii; NMR (400 MHz, dmeo-ab) b 8.01 (aa, U - 8.0, 5.0 Hu, 1H), 7.95 (5, 1H ), 7.50 (yes, 9 - 7.9, 1.5 Hz, 1H), 7.37 (a, U - 1.9

Hz, 1H), 6.50 (a, U - 1.9 Hz, 1H), 4.34 (I, 9 - 7.3 Hz, 2H), 3.46 (y, 9 - 14.4, 9.9 Hz, 1H), 2.66 (a,

U - 10.4, 4.7 Hu, 1H), 1.99 (5, OH), 1.76 (ai, U - 17.9, 8.3 Hz, ЗН), 1.38 (a, U - 12.7 Hz, 9H), 1.30 (a,

U -10.5 Hz, ZN), 1.17 (a, U - 2.3 Hz, ZN), MO-IER t/2 calc. 559.1423, found 560.5 (M--1) Kk;

Holding time: 0.74 min. (Method of RH A).

Stage C: 4-chloro-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (Compound A) o o o ti PO

Ex 7 5

H U same 5 M in - M- m | N

SI M si - MM 7

Solution // tert-butyl-4-(3-I5-(2,6b-dichloropyridine-3-carbonyl)usulfamoyl|pyrazol-1-yl|propyl|- 2,2-dimethylpyrrolidine-i-carboxylate (100 mg, 0 ,1784 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (150 μL, 1.960 mmol) was stirred at room temperature for 4 h. The solvents were removed by evaporation and 2 M MNH in methanol (10 mL) was added, the reaction mixture was stirred for 30 min, then concentrated and dried in vacuum.

The above-mentioned residue was dissolved in dimethylsulfoxide (2 ml) and molecular sieves Z were added

And the reaction mixture was stirred for 10 minutes. Cesium fluoride (85 mg, 0.5596 mmol) and potassium carbonate (78 mg, 0.5644 mmol) were then added, and the reaction mixture was heated at 140 °C overnight. and the filtrate was purified by reversed-phase NRIS-M5 (column Hypa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (рп: 00С-4252-00-АХ) and a double gradient from 50 95 to 99 95 mobile phase B for 15.0 min, mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile. Flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25702) with obtaining 4-chloro-20,20-dimethyl-10Ab6-thia-1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (28 mg, 12 95)

as a white solid. 1H NMR (400 MHz, Spiogothogite-a) b 8.77 (5, 1H), 7.54 - 7.44 (t, 2H), 7.07 (a, U - 2.3 Hz, 1H), 6.48 (0, U - 7.9 Gu, 1H) , 4.36 - 4.24 (t, 1H), 4.06 - 3.85 (t, 1H), 2.67 (i,

U - 8.3 Hu, 1H), 2.14 (dak 17.7, 12.1, 6.2 Hz, 2H), 2.07 - 2.01 (t, 1H), 1.98 - 1.84 (t, 2H), 1.73 (da49, U - 12.1, 5.5, 1.5 Hu, 1H), 1.55 (5, ZN), 1.50 (5, ZN), 1.44 (I, 9 - 12.3 Hu, 1H), 0.86 - 0.69 (t, 1H). MO-IER t/2 calc. 423.1132, found 424.4 (M--1)f; Holding time: 1.76 min. (The method of RH

IN).

Stage 4: 4-chloro-21,21-dimethyl-10Abthia-1,3,9,14,15- pentaazatetracyclo!y17.2.1.02,7.011,15|docosa-2,4,6,11,13-pentane -8,10,10-trione (compound B) o oo

M

5

Uh 7 and o o o

N / ii - M- y si M si yi y y: y U ---3- yr. M- si M pla MN

VosmM

Solution // tert-butyl-4-(3-I3-(2,6b-dichloropyridine-3-carbonyl)usulfamoyl|pyrazol-1-yl|propyl|- 2,2-dimethylpyrrolidine-i-carboxylate (100 mg, 0 .1784 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (150 μL, 1.960 mmol) were stirred at room temperature for 4 hours. After the reaction was complete, the solvents were removed by evaporation and 2

M MNH in methanol (10 mL), and the reaction mixture was stirred for 30 minutes, concentrated, then dried under vacuum. The residue was dissolved in dimethylsulfoxide (2 ml), molecular sieves Z A were added, and the reaction mixture was stirred for 10 min. Cesium fluoride (85 mg, 0.5596 mmol) and potassium carbonate (78 mg, 0.5644 mmol) were then added, and the reaction mixture was heated at 140 C overnight. The reaction mixture was filtered through an Upaytap disk filter (rigadibs 25 TE), and the filtrate was purified by reversed-phase NRI S-M5 (column I ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (rp: 00С -4252-00-АХ) and a double gradient from 50 95 to 9995 mobile phase B for 15.0 min, mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile. Flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 257) to obtain 4-chloro-21,21-dimethyl-10X6-thia-1,3,9,14,15-pentaazatetracycloi17.2.1.02,7.011,15|docose -2,4,6,11,13-pentane-8,10,10-trione (10.2 mg, 4 95) as an off-white solid. 1H NMR (400 MHz, Spioghotopt-a) b 9.16 (5, 1H), 7.76 (y, U - 8.0 Hz, 1H), 7.57 (ad, 9 - 2.1 Hz, 1H), 7.35 (y, 9 - 2.1 Hz , 1H), 6.82 (a, 9 - 8.0

Hu, 1), 4.78 (4, U - 13.6, 4.0 Hu, 1H), 4.41 - 4.29 (t, 1H), 3.20 (1, U - 9.7 Hu, 1H), 2.62 - 2.56 (t, 1H), 2.52 (5, 1H), 2.21 - 2.06 (t, 1H), 1.91 (5, 1H), 1.81 - 1.69 (t, ЗН), 1.63 (5, 4Н), 1.45 (5, ЗН). MO-

IER t/2 calc. 423.1132, found 424.4 (M--1)k; Holding time: 1.9 min. (Method of RH B).

From Example 119: Preparation of 20,20-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9, 14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound 32)

M hu "7 X xx ra 0-І 7MN Vier1 Y u r AKA vo; where -

Stage 1: 20,20-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14 22-pentaazatetracycloi16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound 32)

POM m s Y U z 8 Mn M sOogo.: a she;

Solution 4-chloro-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pental-8,10,10-trione (20 mg, 0.04718 mmol), scandium triflate, 3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|-1H-pyrazole (31.16 mg, 0.1415 mmol) and Man (9.435 mg 60 95 wt., 0.2359 mmol) in dimethylsulfoxide (2.0 ml) were stirred at 140 "C for 16 hours. The reaction mixture was quenched with a few drops of water and filtered through a disk filter UMpaytap (Rigadies 25 TE ), and the filtrate was purified using the reversed-phase HPLC-MS method, using a column I pa C18 (2) (75 x 30 mm, 5 μm particle size), sold by Rpepotepeh (art.: 00С-4252-00-АХ) , a double gradient run from 1-99 96 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile. Flow rate - 50 ml/min, column temperature 2575) C obtaining 20,20-dimethyl-4-(3-12-|(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 22-pentaase atetracyclo|16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (compound 32) (2.4 mg, 8 95) as a white solid. 1H NMR (400 MHz, Spiogothogite-4) b 8.49 (5, 1H), 8.17 (a, Y - 2.7 Hz, 1H), 7.69 (a, Y - 8.3 Hz, 1H), 7.49 (5, 1H), 7.08 (y, 9 -.2.1 Hz, 1H), 7.01 (а,9 - 8.2

Hz, 1H), 5.87 (8, U - 2.7 Hz, 1H), 4.39 (i, U - 7.1 Hz, 2H), 4.35 (5, 1H), 3.94 (I, U - 12.9 Hz, 1H), 2.78 - 2.72 (t, 1H), 2.20 - 2.13 (t, 2H), 2.10 (a, 9 - 7.0 Hu, 2H), 1.99 (Y, U - 10.3 Hu, ЗН), 1.79 - 1.74 (t, 1H), 1.59 (5, ЗН), 1.55 (5, З Н), 1.47 (I, У - 12.0 Hz, 2Н), 1.04 - 1.00 (t, 2Н), 0.77 - 0.73 (t, 2Н). MO-

IER tt/2 calc. 607.2189, found 608.6 (М--1)хк; Holding time: 2.18 min. (Method of RH E).

Example 120: Preparation of (155)-12,12-dimethyl-8-(3-12-|(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9 ,11,19,24-pentaase tetracyclo|18.3.1.05,10.011,15|)hetracose-1(23),5,7,9,29(24),21-hexane-2,2,4-trione (Compound 33) and (158)-12,12-dimethyl-8-(3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 34)

TE I Kk Zhi what he what: where | seams drag gu water

Stage 1: (155)-12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab6-thia-3,9, 11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15|hetracose-1(23),5,7,9,20(24),21-

From hexane-2,2,4-trione (Compound 33) and (15K)-12,12-dimethyl-8-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole-1- yl)-2A6b-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20(24) 21-hexane-2, 2,4-trione (Compound 34) with C | with t M - - |v . o How M M what. dar terta ory rt Tr

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)htetracose-1 (23),5,7,9,20(24), .-21- hexane-2,2,4--rione (90 mg, 0.1420 mmol ) was subjected to chiral NCR chromatography using SpigaiRak A5-H (column 250 x 10 mm, particle size 5 μm) with 18 95 acetonitrile:methanol (90:10; without modifier))/82 95 mobile phase of carbon dioxide at 10 ml/min with obtaining as the first enantiomer for elution, (155)-12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b- thia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 33) (28.6 mg, 64 95); IN NMR (400 MHz, DMSO-ab) b 12.73 (5, 1H), 8.23 (a, U - 2.68 Hz, 1H), 8.01 (a, - 8.3 Hz, 1H), 7.58, 9 - 7.8 Hz, 1H) . , U - 6.9 Hz, 2H), 3.72 (5, 2H), 3.10 (5, 1H), 2.11 -

2.05 (t, 2H), 1.85 (5, 2H), 1.74 (a, U - 8.9 Hz, 2H), 1.43 (a, U - 65.6 Hz, 9H), 1.01 - 0.85 (t, 5H), MO-

IER t/2 calc. 633.2345, found 634.2 (М-а-1)хк; Holding time: 1.85 min. (Method of RH B) apa av

(15H8)-12,12-dimethyl-8-(3-12-1-CypyogoteiNui)susiorgoruCeiohu)-1H-ruga?01-1-yl)-2A6-thia-3,9,11 ,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 34) (29.1 mg, 65 95); IN NMR (400 MHz, DMSO-ab) b 12.73 (5, 1H), 8.23 (y, Y - 2.8 Hz, 1H), 8.01 (a, Y - 8.2 Hz, 1H), 7.58 (ai, y - 8.4, 7.2 Hz, 1H), 7.29 (a, U - 6.9 Hz, 1H), 7.03 (a, y - 7.2 Hz, 2H), 6.63 (y, U - 8.4 Hz, 1H), 6.13 (y, U - 2.8 Hz , 1H), 4.38 - 4.28 (t, 2H), 3.72 (5, 2H), 3.10 (5, 1H), 2.08 (I, U - 7.0 Hz, 2H), 1.96 - 1.68 (t, 4H), 1.51 ( 5, BN), 1.35 (5, 4Н), 0.99 - 0.85 (t, 5Н), MO-IER t/2 calc. 633.2345, found 634.2 (M--1)k; Holding time: 1.85 min. (Method of RH B).

Example 121: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,20 ... shk gunpowder Ver voshi g, vo "o vyuz, . M m se Oi

NA y: y on 5 m y y | 4 | vyvra se | Bivr 5 se Z Moi (in; ak Mo is 4 M | 2 A (in shcha - in kl I 5

Stage 1: tert-butyl 5-(3-cyanopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate d-m (c) c)

My Vos, then with Fr

Tert-butyl-2,2-dimethyl-5-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (650 mg, 1.938 mmol), dimethyl sulfoxide (2 mL), and sodium cyanide (100 mg, 2.041 mmol) were added to a round-bottom flask. The reaction was heated at 80 C overnight.

The reaction mixture was filtered and purified by HPLC (1-99 95 acetonitrile in water with 0.195 hydrochloric acid modifier) to give tert-butyl 5-(3-cyanopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (272 mg, 53 95 ). MO-IER, etc./2 calc. 266.19943, found 211.2 (MA) k; retention time: 1.67 min. (Method of RH B).

Stage 2: tert-butyl 5-(4-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate -k Mn, p

Whoa whoa

Tert-butyl-5-(3-cyanopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (271 mg, 1.017 mmol), methanol (1.50 ml), Raney nickel (100 mg 50 95 mabs) was added to a round-bottomed flask. /vol.) and ammonia (2.80 ml of 7 M, 19.60 mmol). The reaction mixture was purged with nitrogen, a flask of hydrogen (2.050 mg, 1.017 mmol) was added and the mixture was stirred overnight at room temperature.

Additionally, Raney nickel (100 mg, 50 95 wt./vol.) and ammonia (2.80 mL of 7 M, 19.60 mmol) were added and the reaction mixture was stirred for 4 hours. The reaction mixture was filtered and the sediment on the filter was washed with an additional amount of methanol and dichloromethane. The filtrate solution was evaporated to dryness to give tert-butyl-5-(4-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (270 mg, 98 95) as a clear colorless oil. MSO-IER t/: calc. 270.23074, found 271.3 (MAT) k;

Holding time: 1.1 min. (Method of RH B).

Stage 3: tert-butyl 2,2-dimethyl-5-(4-(b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate

MN, oo o /y

M ray

Vosu NA - to NM | t

M and | - A -Sh- M. Zh

M

Vos

M MN

E hr

Potassium carbonate (415 mg, 3.003 mmol), b6-fluoropyridine-2 sulfonamide (170 mg, 0.9650 mmol) and a solution of tert-butyl-5-(4-aminobutyl)-2,2-dimethyl-pyrrolidine- 1-carboxylate (270 mg, 0.9985 mmol) in dimethyl sulfoxide (3 mL). The reaction mixture was placed in an oil bath preheated to 80 °C and allowed to stir overnight. The reaction mixture was filtered and purified by HPLC (1-99 95 acetonitrile in water with 0.1 96 hydrochloric acid modifier) to give // tert-butyl -2,2-dimethyl-5-(4-((b-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (155.2 mg, 38 95). MO-IER t/2 cal. 426 ,23007, found 427.3 (M--1) k, retention time: 1.71 min (Method RH B).

Stage 4: tert-butyl 5-I4-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

KU Y Do

She em MU si p" em Mi si I

Me Mn kp as Me mn aa vo e- va

2-Chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (166.0 mg, 0.4418 mmol), carbonyldiimidazole ( 71 mg, 0.4379 mmol) and tetrahydrofuran (2.0 ml). The reaction mixture was heated to 45 "C for 2 hours, then a solution of tert-butyl-2,2-dimethyl-5-(4-(b-sulfamoyl) was added -2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (155.2 mg, 0.3638 mmol) in tetrahydrofuran (2.0 mL), then 1,8-diazabicyclo/5.4.F)undec-7-ene (165 μL, 1.103 mmol) and the reaction mixture was allowed to stir at room temperature overnight.The reaction mixture was filtered and purified using

HPLC (30-99 95 acetonitrile in water with 0.1 96 hydrochloric acid modifier), obtaining tert-butyl-5-I(A-((6-(2-chloro-6-(3-(2-P1-( trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-

Z carbonyl|Isulfamoyl|-2-pyridylIamino|butyl|-2,2-dimethylpyrrolidine-I-carboxylate (126 mg, 44 95) was isolated as a white solid. MO-IER Ip/2 calc. 783.27924, found 784.5 (MA) k; retention time: 1.9 min. (method RH b).

Stage 5: 2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-2-yl)butylamine|-2-pyridyl|sulfonyl/|-6-(3-(2-

P-"(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (o) mM (9) ex/P 5-47 is. si -ya o uk MU ts Iv oh Kk x I

Tert-butyl 5-(A-I(6-Ce-chloro-6-I3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl| -2- pyridylamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (126 mg, 0.1607 mmol), dichloromethane (2 mL), and hydrochloric acid (400 μL of 4 M in dioxane, 1.600 mmol).The reaction was stirred at at room temperature for 1 h. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-M-I((6-(4-(5,5-dimethylpyrrolidine-2- yl)butylamine|-2-pyridyl|sulfonyl|-6-3-(2-P-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (105 mg, 9695). MO-IER t /2 calcd 683.2268, found 684.5 (M-A1)g, retention time: 0.79 min (Method RH B).

Stage 6: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,20,25- pentaazatetracyclo|19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25) 22-hexane-2,2,4-trione (Compound 37) ooo z M z ry

N | y M zha |v m u y pe a Kk sh-- mn g

Potassium carbonate (107 mg, 0.7742 mmol), cesium fluoride (35 mg, 0.2304 mmol) and a solution of 2-chloro-M-I((6-(4-(5,5-dimethylpyrrolidine-2 -yl)butylamine|-2-pyridyl|sulfonyl|-6-

13-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (105 mg, 0.1535 mmol) in dimethyl sulfoxide (1.8 mL). The reaction mixture was heated in a sealed test tube overnight at 150 °C. The reaction mixture was quenched with saline and extracted with ethyl acetate.

The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by HPLC (30-99 95 acetonitrile in water with 0.1 96 hydrochloric acid modifier) to give 12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)- 1 H-pyrazol-1-yl)-2A6b-thia-3,9,11,20,25- pentaazatetracyclo|19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25 ) 22-hexane-2,2,4-trione (compound 37) (27 mg, 25 90). MO-IER tp/2 calcd. 647.2502, found 648.2 (M--1) w; retention time : 1.97 min (method RH B).

Example 122: Preparation of 8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracycloyl 17.3.1.111,14.05 ,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (hydrogen chloride salt) (Compound 38) o M GI KU nm xx hu m hu z on p se -Y M si MN sh- Mn

M y y o oo

Shchi) I xx "7 sh yu-47 her 7 Iv -- M se I sh- / M M M " NSI

Mn

Stage 1: tert-butyl 4-(3-((6-(2-chloro-6-3-K(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridin-3-carbonyl| Isulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

(c) M o oy i on | N

In OH tre Y sh-a m si Mn ot o shd- MN

M y 2-Chloro-6-I3-K(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (200 mg, 0.5431 mmol) and carbonyldiimidazole (88 .06 mg, 0.5431 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at 50 "C. then tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2 -pyridyl)amino|propyl|pyrrolidine-i-carboxylate (179.3 mg, 0.4345 mmol) followed by 1,8 diazabicycloi5.4.F)undec-7-ene (124.0 mg, 121.8 μl , 0.8147 mmol), and the reaction mixture was heated at 50 "C for 18 hours. The reaction was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride, followed by washing with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 70 95 ethyl acetate in hexane to give tert-butyl-4-IZ-C(6 -(2-chloro-6-I3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridin-3-carbonyl|isulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine -i-carboxylate (206 mg, 51 95). MS-IER p/2 calcd 743.3232, found 744.7 (M--1) g; retention time: 0.95 min (LC method

AND).

Stage 2: 2-chloro-M-((6-I3-(5,5-dimethylpyrrolidin-3-yl/upropylamino|-2-pyridyl|sulfonyl|)-6-(3- hydroxypyrazol-1-yl)upyridin- 3Z-carboxamide о в6о О оо

M XM//

M - My M - Mich

Gee! / M M SI - - on;t no and M M SI at o MN and MN /

Vos

To a solution of tert-butyl-4-I3-C(6-C2-chloro-6-(3-(2.,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl |-2- pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-i-carboxylate (25 mg, 0.03359 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (19.16 mg, 12.95 μL, 0, 1680 mmol) at 0 °C and this mixture was stirred for 30 min (reaction mixture 1). Separately, to a solution of tert-butyl-4-

IZ-Kb-Ce-chloro-6-I3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|-2-pyridylIamino|propyl|-2,2 -dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in dioxane (1 mL) was added hydrochloric acid (42.00 μl 4 M, 0.1680 mmol) at 0 "C, and the mixture was stirred for 30 min (reaction mixture 2).Separately, a solution of tert-butyl-4-IZ3-KC6-Ce-chloro-6-I3-(2,2,3,3-tetramethylcyclopropyl)methoxy|pyrazol-1-yl|pyridin-3-carbonyl|isulfamoyl |-2-Pyridylamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in 2,2,2-trifluoroethanol (1.680 g, 1.224 mL, 16.79 mmol) containing 1 95 trifluoroacetic acid, stirred for 30 min (reaction mixture 3). Separately to a solution of tert-butyl-4-III-C(6-(2-chloro-6-I3-(2,2,3,3-tetramethylcyclopropyl)methoxy) |pyrazol-1-yl|pyridine-3-carbonyl|isulfamoyl|-2-pyridylyamino|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in toluene (1 ml) was added to silica gel ( 100 mg) and the mixture was heated at 907 for 24 h (react tion mixture 4). All four reaction mixtures were combined and purified by the reverse-phase HPLC-MS method using a column Ipa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (product number: 00С-4252-00-АЧ ) and a double gradient from 20 95 to 80 95 mobile phase B for 15.0 minutes (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and the temperature of their column 2570) to obtain 2-chloro-M-((6-I|3-(5,5-dimethylpyrrolidin-3-ylpropylamino|-2-pyridyl|sulfonyl|/|-6-(Z- Hydroxypyrazol-1-yl)pyridine-3-carboxamide (42 mg, 47 95).IN NMR (400 MHz, Meippaoi!-44) b 8.31 (a, 9 - 2.9 Hz, 1H), 8.00 (a, U - 8.4 Hz, 1H), 7.72 - 7.63 (t, 2H), 7.30 (ai, 9 - 7.2, 0.8 Hz, 1H), 6.84 (aa, 9 - 8.6, 0.8 Hz, 1H), 5.97 (y, 9 - 2.68 Hz , 1H),

3.50 (da, U - 11.8, 8.4 Hz, 21H), 3.41 (ar, U - 20.3, 6.7 Hz, 2H), 2.93 (da, U - 11.8, 9.1 Hz, 1H), 2.54 (ai, U - 16.6, 8.3 Gu, 1H), 2.09 (aa, U 2 13.1, 7.5 Hz, 1H), 1.70 - 1.59 (t, 2H), 1.59 - 1.48 (t, 2H), 1.45 (5, ЗН), 1.37 (5, ЗН ). MO-IER t/2 calc. 533.1612, found 534.5 (M'-1)x; retention time: 0.45 min. (Method of RH A).

Stage 3. 8-(3-Hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2Abthia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (hydrochloride salt) (Compound 38) o o o

І ОО о о х и сх Х

N | Eh M Eh

Mo. 2 M and | and no that M SI ---zhzhk M. r M. 2 o MN o " in sh- MN

NS

MN

To a solution of 2-chloro-M-I((6-I3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-pyridyl|sulfonyl|-6-(3-hydroxypyrazol-1-yl)ypyridin- 3-carboxamide (42 mg, 0.07865 mmol) in dimethylsulfoxide (2.0 mL) was added through molecular sieves Z A and the mixture was stirred at room temperature for 15 min. Cesium fluoride (11.95 mg, 0.07865 mmol) was then added ) and potassium carbonate (10.87 mg, 0.07865 mmol), and the reaction mixture was heated at 140 °C overnight. The reaction mixture was filtered through a UUPytap disc filter (Rigadies 25 TE), and the filtrate was purified by reversed-phase HPLC-MS , using a Hypa C18 column (2) (75 x 30 mm, particle size 5 μm) sold by the Rpepotepeh company (рп: 00С-4252-00-АХ) and a double gradient from 30 95 to 80 95 mobile phase B for 15, 0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature "- 25 "C) with obtaining 8-( 3-hydroxy-1H-pyrazol-1-yl)-12,1 2-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo!/17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane -2,2,4-trione (hydrochloride salt) (Compound 38) (2.5 mg, 17 Fo) as a white solid. IN NMR (400 MHz, Mefiapo!-a4) b 8.21 (a, 9 - 2.7 Hz, 1H), 7.84 (a, - 8.2

Hz, 1TN), 7.57 - 7.51 (t, 1Н), 7.16 (y, 9 - 7.2 Hz, 1Н), 6.92 (y, 9 - 8.3 Hz, 1Н), 6.67 (y, U - 8.5 Hz, 1Н), 5.87 (y, 9. - 2.7 Hz, 1H), 4.10 - 4.00 (t, 1H), 3.66 - 3.49 (t, 1H), 3.09 - 3.00 (t, 1H), 2.90 - 2.82 (t, 1H), 2.66 (a, U 2 11.1 Gu, 1H), 2.24 - 212 (t, 1H), 1.92 - 1.82 (t, 1H), 1.66 (5, ЗН), 1.59 (5, ЗН), 1.49 - 1.39 (t, 2Н ), 0.95 - 0.83 (t, 2H). MO-IER t/2 calc. 497.1845, found 498.5 (Mai1)k; retention time: 1.48 min. (Method of RH E).

Example 123: Preparation of 21,21-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14, 23-pentaazatetracyclo|1 7.2.1.111,14.02,7|gricose-2,4,6,11(23),12-

From pentane-8,10,10-trione (Compound 39) o o o o

Osm periy vier1 Kh Zhe ol Y nya y t, nm V , and | about him Vier2

Mn What o-- TM m sy ry o

N. M

5-4 Me still where r | sha A 7 (e)

Stage 1: tert-butyl /2,2-dimethyl-4-I(4-(3-sulfamoylpyrazol-1-yl)butyl|pyrrolidine-1-carboxylate oo oo

OM M h

VosmMra ra: bro- o od tert-Butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-i-carboxylate (848 mg, 2.426 mmol) and 1H-pyrazole-3-sulfonamide (361.5 mg , 2.457 mmol), and then potassium carbonate (1.2 g, 8.683 mmol) was dissolved in M,M-dimethylformamide (9.0 mL) and stirred at 60°C in a sealed 20-mL vial for 20 hours (SHRI C indicates for conversion to the expected product plus a secondary less polar second peak with the same mass as the secondary regioisomer byproduct.) Cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL), combined organic layers, washed with water (2 x 100 ml), dried (sodium sulfate), filtered and concentrated.

The brown residue was purified by silica gel chromatography using a gradient of 100 95 hexanes to 10095 ethyl acetate to give tert-butyl-2,2-dimethyl-4-|4-(3- sulfamoylpyrazol-1-yl)butyl|pyrrolidine-1-carboxylate (427 mg, 4495). 1H NMR (400 MHz, dmeoo-ab) b 7.87 (a, 9 - 2.3 Hz, 1H), 7.37 (5, 2H), 6.56 (j, y - 2.3 Hz, 1H), 4.15, 9 - 7.1 Hz, 2H ), 3.53 (ad, U - 11.2, 5.4 Gu, 1H), 2.76 (ai, U - 22.3, 10.8 Hz, 1H), 2.05 (5, 1H), 1.94 - 1.83 (t, 1H), 1.82 - 1.73 ( t, 2Н), 1.40 - 1.35 (t, 12Н), 1.33 (5, ЗН), 1.30 (а, У - 2.5 Hz, 1Н), 1.23 (5, 4Н). MO-IER tp/2 calc. 400.21442, found 401.2 (M--1)k; Holding time: 1.64 min. (The method of RH is).

Stage 2: tert-butyl 4-I4-I3-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|pyrazole-1 -yl|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

M I ik y xx V y "o Y m so so Ko; t-M - M -Mm --.Y moe 0-Y TOM tes 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (500 mg, 1.331 mmol) and carbonyldiimidazole (215 mg, 1.326 mmol) were combined in tetrahydrofuran (8.0 mL) and stirred for 120 min at 50 C. then tert-butyl-2,2-dimethyl-4-14-(3-sulfamoylpyrazol-1-yl)butyl|pyrrolidine-1-carboxylate (423 mg, 1.056 mmol) was added, and then 1,8-diazabicyclo| 5.4.0)undec-7-ene (350 μl, 2.340 mmol), and the reaction mixture was heated at 50 "C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M citric acid solution, and then with brine. The organic layers were separated , dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 9095 ethyl acetate in hexane, with

Obtained as a white solid tert-butyl-4-I4-3-(2-chloro-6-I3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl| sulfamoyl|pyrazol-1-yl|Ibsutyl|-2,2-dimethylpyrrolidine-1-carboxylate (587 mg, 73 90). MO-IER t/72 calcd. 757.2636, found 758.2 (M--1) k; Retention time: 2.37 min (Method RH E).

Stage 3. /21,21-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9, 14, 23-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (Compound 39) Eat your food; in; 5-47 M in Ku 5-07 Ex M-m tert-Butyl 4-I4-IZ-C(2-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl |pyridine-

3-Carbonyl|Isulfamoyl|pyrazol-1-yl|brutil|-2,2-dimethylpyrrolidine-1-carboxylate (580 mg, 0.7649 mmol) was dissolved in dichloromethane (12 mL) and hydrochloric acid (6.0 Jr

AM in dioxane, 24.00 mmol) and stirred at room temperature for 1 hour. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2M sodium carbonate (5 ml) was added, obtaining a pH of - 10. The organic layer was removed and the aqueous layer was additionally washed with ethyl acetate (2 x 10 ml), the organic layers were combined, washed with saline, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. This material was combined with potassium carbonate (550 mg, 3.980 mmol), cesium fluoride (185 mg, 1.218 mmol), Z A molecular sieves, and dimethyl sulfoxide (12 mL) in a nitrogen-purged, capped vial heated to 150 °C. .and stirred for 18 hours.

It was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and washed with 1M citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexane to give 21,21-dimethyl-4-(3-( 2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 23- pentaazatetracyclo!y17.2.1.111,14.02,7|gricose- 2,4,6,11(23),12-pentane-8,10,10-trione (compound 39) (176.9 mg, 37 95). IN NMR (400 MHz, DMSO-46) b 12.59 (5 . (y, 9 - 2.7 Hz, 1H), 4.30 (ad, 9 - 15.9, 9.0 Hz, 4H), 2.73 (a, U - 22.6, 11.0 Hz, 2H), 2.31 - 2.18 (t, 1H), 2.18 - 2.03 (t, ЗН), 2.02 - 1.92 (t, 1Н), 1.89 (ai, U - 11.9, 5.5 Hz, 1Н), 1.67 (5, 1Н), 1.61 (5, ЗН), 1.60 - 1.54 (t, 1H), 1.52 (5, ЗН), 1.48 (a, U - 12.4 Hu, 1H), 1.16 - 1.03 (t, 1H), 0.99 - 0.93 (t, 2H), 0.90 (y, U - 10.9 Hu, 2H ), 0.77 (5, 1H).

MO-ER t/2 calc. 621.2345, found 622.4 (M--1) xx; retention time: 2.2 min. (Method of RH E).

Example 124: Preparation of 7,7-dimethyl-11-(3-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10, 16,22-pentaazatetracyclo(|16.3.1.04,8.09,14|docosa-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 41) and Mo, Mn , o Mn, o. Mn, o- Zier1 - TSI Zivr2 faith from faith Faith 5 cho nom wk Vosm

M u / M o nd xx Zier b nt hu s on vier 7

M M SI

I ate it 7

Vos o oy (9) oy

M - M and M. 2 M and 0-0 M si Zivr 8 0-0 M SI Zier 9

Vos ni o oi

B with d"

MM | ME m M 2 0-47 o ! -7 U

Stage 1: 5,5-dimethyl-1-trimethylsilyloxypyrrolidine-2-carbonitrile

Od in pa

M

- - - 8

Trimethylsilylformonitrile (30.93 g, 39 mL, 311.8 mmol) was added to 2,2-dimethyl-1-oxido-3,4-dihydropyrrol-1-ium (23.31 g, 206.0 mmol) in dichloromethane ( 920 ml) and the mixture was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure under safe conditions to obtain the desired product 5,5-dimethyl-1-trimethylsilyloxypyrrolidine-2-carbonitrile (44.04 g, 101 95) as a crude amber oil, which was used directly in the next step. MO-IER tp/2 calc. 212.13, found 213.2 (M-AT) zhk; retention time: 2.325 min. (Method РХ 1).

Stage 2: 1-hydroxy-5,5-dimethylpyrrolidine-2-carboxamide

M o MN, that with - yu» nos o-. M

M

5,5-Dimethyl-1-trimethylsilyloxypyrrolidine-2-carbonitrile (13 g, 61.22 mmol) was slowly added to sulfuric acid (160.1 g, 87 mL, 1.632 mol), cooled in an ice bath and allowed to stir at room temperature From The reaction mixture was diluted with ice (400 mL) and the resulting mixture was slowly neutralized with solid sodium hydroxide (125 g, 3.125 mol) divided into 3 portions (the last two portions were dissolved in water (75 mL)), and the pH was verified to be from weak main to neutral. The mixture was extracted with ethyl acetate (3 x 500 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure, then dried in vacuo to give the desired product, 1-hydroxy-5,5-dimethylpyrrolidine-2-carboxamide (8.51 g, 88 .) in the form of a pale yellow powder. TN NMR (300 MHz, DMSO-ab) mp 0.92 (5, ЗН), 1.07 (5, ЗН), 1.38-1.59 (t, ЗН), 1.91-2.09 (t, 1Н), 3.13-3.22 (t, 1Н ), 6.92 (ru. 5., 1H), 7.08 (Brg. 5., 1H), 7.62 (5, 1H). MO-IER t/ calc. 158.198, found 159.2 (M--1) zhk; holding time: 1.561 min. (Method РХ 1).

Stage 3: 5,5-dimethylpyrrolidine-2-carboxamide about MH. o MH, - - -k pom НМ 1-hydroxy-5,5-dimethylpyrrolidine-2-carboxamide (8.51 g, 53.79 mmol), dissolved in methanol (200 mL), was stirred overnight with Raney nickel (8 .7 g, 148.2 mmol) and gaseous hydrogen from an inflated cylinder with a capacity of 8 liters of gas. After 5 h, Raney nickel (8 g, 136.3 mmol) was added and the mixture was stirred overnight. Additional Raney nickel (9.69 g, 165.1 mmol) was added to the mixture and the mixture was further stirred for 3 days. To the reaction mixture

Raney nickel (9.5 g, 161.9 mmol) was added and the mixture was stirred for 4 hours. The reaction mixture was decanted, the solid nickel was washed with methanol (3 x 250 ml), a certain amount of celite was added to the combined methanol fraction, then it was filtered through celite and the precipitate was washed with methanol. The combined filtrate was concentrated under reduced pressure to give the desired product, 5,5-dimethylpyrrolidine-2-carboxamide (7.29 g, 95595) as a beige solid. 1H NMR (300 MHz, SOSIS) mp 1.16 (5, ZN), 1.19 (5, ZN), 1.45-1.72 (t, 2H), 1.81 (Bg. 5., 1H), 1.92-2.09 (t, 1H), 2.18-2.40 (t, 1H), 3.78 (aa , 9U-9.4, 6.2 Hz, 1H), 5.70 (Bg. 5., 1H), 7.45 (rg. o 5., 1). MO-IER t/72 calc. 142.1106, found 143.2 (M--1)4; retention time: 0.31 min. (Method РХ 1).

Stage 4: tert-butyl 5-carbamoyl-2,2-dimethyl-pyrrolidine-1-carboxylate o) Mn, o) Mn, ---26ieo

NM VosmM

Di-tert-butyldicarbonate (21 g, 96.22 mmol) was added to 5,5-dimethylpyrrolidine-2-carboxamide (7.25 g, 50.98 mmol) dissolved in dioxane (140 mL), and water was added to the mixture. (50 mL), then the mixture was allowed to stir at room temperature overnight. Sodium hydroxide (1.84 g, 46.00 mmol) dissolved in water (100 mL) was added to the mixture and the mixture was allowed to stir for 2 minutes, then ethyl acetate (200 mL) was added and the aqueous phase was discarded.

The organic fraction was dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure. The resulting oil partially solidified when kept in a vacuum. The solid was triturated in heptane (50 ml), filtered and washed with an additional amount of heptane (3 x 100 ml), then dried in vacuo to give tert-butyl-5-carbamoyl-2,2-dimethyl-pyrrolidine-1-carboxylate (10 .95 g, 89 95) in the form of a white powder. 1-1H NMR (300 MHz,

SOSIZ) mp 1.33 (Be. 5., ZN), 1.48 (ru. 5., 12H), 1.70-2.34 (t, 4H), 4.16-4.48 (t, 1H), 5.30-5.58 (t, 1H), 5.71-7.03 (t, 1H). MO-IER t/; calculation 242.163, found 143.2 (M'-1) w; retention time: 1.67 min. (Method RH I).

Stage 5: tert-butyl 5-(aminomethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate about Mn, Mn; - - -with

BosM BosM tert-Butyl-5-carbamoyl-2,2-dimethyl-pyrrolidine-1-carboxylate (5.3 g, 21.87 mmol) was added to borane-tetrahydrofuran (102 mL of 1 M in tetrahydrofuran, 102.0 mmol) and after the evolution of hydrogen stopped, the reaction mixture was heated to 70 °C overnight. The reaction mixture was slowly quenched with concentrated ammonium chloride (1 mL). The mixture was then transferred to a 1 L round-bottom flask containing deionized water (110 mL). With vigorous stirring iodine (100 mg, 0.020 mL, 0.394 mmol) was added and the mixture was allowed to stir in air for 2 h.

The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified on silica gel using a gradient of 10 95 to 100 95 methanol in dichloromethane. Additional material was extracted by applying ammonium hydroxide (2 ml) to the top of the column followed by elution with pure methanol (carried out 3 times). This gave tert-butyl-5-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.19 g, 24 95) as an amber oil. 13 NMR (300 MHz,

From SOSIZ) pp 1.27 (B. 5., ZN), 1.33-1.51 (t, 14H), 1.62-1.76 (t, 2H), 1.78-2.03 (t, 2H), 2.53 (da, 912.6, 8.2 Gu, 1H), 2.73-3.00 (t, 1H), 3.61-3.99 (t, 1H). MO-IER tp/2 calc. 228.331, found 229.3 (M.-1) xx; retention time: 1.33 min. (Method RH I).

Stage 6: tert-butyl 2,2-dimethyl-5-((6b-sulfamoyl-2-pyridyl)amino|methyl|pyrrolidine-1-carboxylate

МН оо 7 Kf я хи ра: nm -х и NA | and A - I - 2

VosM M. M.

E MN and 7

To tert-butyl-5-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (140 mg, 0.6131 mmol) and b-fluoropyridine-2-sulfonamide (108.0 mg, 0.6131 mmol) in dimethyl sulfoxide (1.179 mL) was added potassium carbonate (86.43 mg, 0.6254 mmol), and the mixture was stirred at 100 "C for 20 h, then allowed to cool to room temperature. Diluted with ethyl acetate and poured into 1 M citric acid. The layers were separated, then the organic layer was washed with saturated aqueous saline, dried (sodium sulfate), filtered and concentrated to a yellow foam, which was purified by chromatography on silica gel using a slight gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 2,2-dimethyl- 5-|(6β-sulfamoyl-2-pyridyl)amino|methyl|pyrrolidine-1-carboxylate (115.6 mg, 49 95) as a white solid.

MO-ER t/2 calc. 384.18314, found 385.4 (M--1)k; retention time: 0.62 min. (Method of RH A).

Stage 7: tert-butyl 5-((C6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino) |methyl/|-2,2-dimethyl-pyrrolidine-1-carboxylate

B Ge) s Ii M he -ya M. - 0-І M si

Mn roz shk: y Kk A Mn

Es

Vos -0

In a 20 ml vial, 2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl pyridine-3-carboxylic acid (113.0 mg, 0.3007 mmol) and carbonyldiimidazole (53.44 mg, 0.3296 mmol) were combined in tetrahydrofuran (1.659 mL) and stirred uncovered for 120 min at 50 C. Tert-butyl-2,2-dimethyl-5-|(b-sulfamoyl -2- pyridyl)amino|methylIpyrrolidine-1-carboxylate (115.6 mg, 0.3007 mmol) in tetrahydrofuran (2.213 mL) followed by the addition of 1,8-diazabicyclo|5.4.O1undec-7-ene (94.25 mg , 92.58 μl, 0.6191 mmol), and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with brine.

The organics were separated, dried over sodium sulfate, filtered and evaporated, then purified using reversed-phase HPLC-MS using a column

Hypa C 18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (рп: 00С-4252-00-

AX) and a double gradient from 30 9o to 99 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and the temperature of the column - 25 "C) to obtain tert-butyl 5-|(6-((2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl |Ipyridine-3-carbonyl|sulfamoyl|-

Zo 2-pyridylamino|methyl|-2,2-dimethylpyrrolidine-1-carboxylate (119.2 mg, 5395). MO-IER t/7 calc. 741.2323, found 742.2 (M--1) k; retention time: 0.88 min. (Method of RH A).

Stage 8: 2-chloro-N-(6-(5,5-dimethylpyrrolidin-2-yl)umethylamino|-2-pyridyl|sulfonyl|)-6-(3-(2-

P-"(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide her PO

M. | 2 M M 2 Mich

Gee! and M M si o and M M si ven MN ot ven MN ko, Es tert-butyl 5-((6-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1 -yl|pyridine-

3-Carbonyl|Isulfamoyl|-2-pyridylyamino|methyl|-2,2-dimethylpyrrolidine-1-carboxylate (119.2 mg, 0.1606 mmol) was dissolved in dichloromethane (520.2 μL) and trifluoroacetic acid ( 840.1 mg, 567.6 μl, 7.368 mmol) and stirred the resulting mixture at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, redissolved in dichloromethane and hexane (1:1), and then the material was evaporated to dryness under reduced pressure and placed under vacuum overnight to give 2-chloro-M-(6-(5,5- dimethylpyrrolidin-2-yl)umethylamino|-2-pyridyl|sulfonyl|-6-I3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (92.9 mg, 90 95). MO-IER t/2 calculated 641.1799, found 642.2 (MAT) Kk;

Holding time: 0.63 min. (Method of RH A).

Stage 9: 7,7-dimethyl-11-(3-12-11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo |16.3.1.04,8.09,14|docose-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 41)

She is in PO

5-47 MA o -x ky, 1, - 0-7 ni

To the solution of 2-chloro-M-(6-(5,5-dimethylpyrrolidin-2-yl)umethylamino|-2-pyridyl|sulfonyl|)-6-(Z3-(2-P-"trifluoromethyl)cyclopropyl|ethoxy| pyrazol-1-yl|pyridine-3-carboxamide (92.9 mg, 0.1447 mmol) in dimethyl sulfoxide (3.716 mL), potassium carbonate (99.99 mg, 0.7235 mmol) was added,

C5E (26.37 mg, 0.1736 mmol) and a small amount of molecular sieves Z A. The resulting mixture was sealed, heated to 150 °C and stirred overnight. It was cooled to room temperature, filtered and purified using the reverse HPLC-MS method phase using a Hypa C 18 column (2) (75 x 30 mm, particle size 5 μm), which is sold

Rpepotepeh (рп: 000-4252-0О0-АЧ) and a double gradient from 30 95 to 9995 of mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 22570). The combined fractions containing the product were removed by acetonitrile on a rotary evaporator, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate (1X), dried (sodium sulfate), filtered and concentrated to obtain 7,7-dimethyl-11-(3-4 -2-P1-("trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-1 7A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.04,8.09,14|docosa- 1(22),9,11,13,18,20-hexane-15,17,17-trione (compound

A1) (27.6 mg, 31 95) as a white solid. MO-IER Ip/7 calc. 605.2032, found 606.0 (MAT) k; retention time: 1.89 min. (Method of RH B).

Example 125: Preparation of 21,21-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 ,23-pentaazatetracyclo|1 7.2.1.111,14.02,7|gricose-2,4,6,11(23),12- pentane-8,10,10-trione (enantiomer 1) (compound 44) and 21,21 -dimethyl-4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 23- pentaazatetracycloyl17.2.1 .111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 45) o 5 o 5 o och Y

Stage (1:0/21,21-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3, 9,14, 23-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (compound 44) and 21,21-dimethyl-4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 23- pentaazatetracyclo! |17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 45) o i o i o z i

Racemic /-21,21-dimethyl-4-(3-12-(11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 23-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (160 mg, 0.2548 mmol) was subjected to chiral NKR- chromatography using

SNigaiRak AB-N (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 2595 acetonitrile: methanol (90:10)/75 96 carbon dioxide at 70 ml/min, with obtaining 21 as the first eluted enantiomer, 21-dimethyl 4-(3-2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14 23-pentaazatetracycloyl17.2.1.111 ,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (compound 44) (65.8 mg, 82 95) as a white solid substances; MO-IER t/: calc. 621.2345, found 622.4 (Ma1)-; Retention time: 2.2 min. -10A6-thia-1,3,9,14,23-pentaazatetracyclo|1 7.2.1.111,14.02,7|gricose-2,4,6,11(23),12- pentane-8,10,10-trione (enantiomer 2) (Compound 45) (70.8 mg, 8995) as a white solid; 1H NMR (400 MHz, DMSO-ab6) b 12.59 (5, 1H), 8.21 (a, 9U - 2.8 Hz, 1H), 7.99 (c, 1H), 7.77 (a, 9U - 7.2 Gu, 1H), 7.02 - 6.80 (t, 2H), 6.12 (9, 9U - 2.7 Gu, 1H), 4.44 - 4.19 (t, 4H), 2.70 (a,

U - 21.3 Hz, 2H), 2.20 (5, 1H), 2.08 (1, U - 7.1 Gu, 2H), 2.00 (a, U - 6.6 Hz, 1H), 1.89 (ai, 9 - 11.9, 5.6 Hz, 1H), 1.67 (y, 9 - 5.7 Gu, 1H), 1.61 (5, ЗН), 1.61 - 1.53 (t, 2Н), 1.52 (5, ЗН), 1.48 (a,

At -12.2 Hz, 1H), 1.18 - 1.04 (t, 1H), 1.00 - 0.93 (t, 2H), 0.89 (5, 2H), 0.77 (5, 1H). MO-IER t/27 calc. 621.2345, found 622.4 (M--1)k; Retention time: 2.2 min (method RH E).

Example 126: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,20 ,25-pentaazatetracyclo|19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 1) (Compound 46) and 12,12-dimethyl-8-(3-12-|1-

Zo (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,20,25- pentaazatetracycloY19.3.1.05,10.011,15|pentacose-1(24), 5,7,9,21(25),22-hexane-2,2,4-trione (enantiomer 2) (Compound 47) o B He) oi o y

Stage 1: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,20,25- pentaazatetracyclo|19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25) 22-hexane-2,2,4-trione (enantiomer 1) (Compound 46) and 12,12 -dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,20,25- pentaazatetracyclo|19.3. 1.05,10.011,15|pentacose-1(24),5,7,9,21(25) 22-hexane-2,2,4-trione (enantiomer 2) (Compound 47) o Y o i o c 12, 12-dimethyl-8-(3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2 A // b-thia- 3,9,11,20,25-pentaazatetracyclo| 19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25),22-hexane-2,2,4-trione (23 mg, 0.03320 mmol) was subjected to chiral NKR- chromatography using

SpigaI!Rak A5-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 18 95 acetonitrile:methanol (90:10; without modifier))/82 95 carbon dioxide at 10 ml/min, which gives as of the first eluted enantiomer, 12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,20 ,25- pentaazatetracyclo|19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25) 22-hexane-2,2,4-trione

(enantiomer 1) (Compound 46) (6.9 mg, 64 95); MO-IER t/z calc. 647.2502, found 648.3 (M--1) k;

Retention time: 1.97 min (LC method B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl )-2A6-thia-3,9,11,20,25- pentaazatetracyclo|19.3.1.05,10.011,15|pentacose-1(24),5,7,9,21(25) 22-hexane-2,2 ,4-trione (enantiomer 2) (compound 47) (6.8 mg, 63 95); MO-IER tp/2 distr. 647.2502, found 648.3 (M-H1) k;

Retention time: 1.97 min (method RH B).

Example 127: Preparation of 7,7-dimethyl-11-(3-(2-/1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10, 16,22-pentaazatetracyclo(|16.3.1.04,8.09,14|docosa-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (compound 50) and 7,7-dimethyl-11-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-1 7A6-thia-2,8,10,16,22- pentaazatetracyclo |16.3.1.04,8.09,14|docose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (Compound 51) b o o o o o o o o

Stage 1: 7,7-dimethyl-11-(3-12-11-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo |16.3.1.04,8.09,14|docose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 1) (Compound 50) and 7,7-dimethyl- 11-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-1 7A6-thia-2,8,10,16,22- pentaazatetracyclo|16.3.1.04,8.09 ,14|docose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (Compound 51)

B on Y 4

Racemic 17,7-dimethyl-11-(3-2-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16, 22- pentaazatetracyclo|16.3.1.04,8.09,14|docose-1(22),9,11,13,18,20-hexane-15,17,17-trione (26 mg, 0.04246 mmol) was subjected to chiral resolution using NKR chromatography using SpigaiaRak A5-H (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 32 95 acetonitrile/methanol (90:10; without modifier)/68 95 carbon dioxide at 10 ml/min (vol injection volume - 70 μl of a 24 mg/ml solution in acetonitrile/methanol (90:10)) with 7,7-dimethyl-11-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy) as the first eluted enantiomer -1 H-pyrazol-1-yl)-1 7A6-thia-2,8,10,16,22-pentaazatetracyclo|16.3.1.04,8.09,14|docosa-1(22),9,11,13,18 ,20-hexane-15,17,17-trione

Zo (enantiomer 1) (compound 50) (11.8 mg, 92 95) as a white solid; MO-IER t/: calc. 605.2032, found 606.3 (M-- 41); Retention time: 1.93 min. )-17A6-thia-2,8,10,16,22-pentaazatetracyclo(|16.3.1.04,8.09,14|docosa- 1(22),9,11,13,18,20-hexane-15,17, 17-trione (enantiomer 2) (compound 51) (12.8 mg, 100 9o) as a white solid; MO-IER Ip/2 calcd. 605.2032, found 606.3 (M 1)xc; Retention time : 1.93 min (method RH B).

Example 128: Preparation of (14K)-8-I(3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18, 23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 65) its M Y Kt / , 5 M t oh m y o-i tm M M m Na o o o

Stage (1: (14K)-8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 65)

Ii M p KI i mu - mah t M ro M o-y4yj 7 mm m m M mm m a 0521 o 53

Racemic 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo|1 7.3.1.111 ,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione chiral separation using NKR chromatography using SpPiga!/Rak

AB-H (250X21.2 mm column, particle size 5 μm) with a mobile phase of 3895 acetonitrile:methanol (90:10))/62 956 carbon dioxide at 70 ml/min, with obtaining (14K)- as the first eluted enantiomer 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05, 10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 65) (51.2 mg, 36 95) as a white solid . 1TH NMR (400 MHz, Spiogothogite-a) b 10.10 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 8.06 (a, 9U - 8.2

Hz, 1H), 7.55 (5, 1H), 7.50 (a, 9U - 6.8 Hz, 1H), 7.28 (5, 1H), 6.57 (5, 1H), 5.91 (a, U - 2.7 Hz, 1H), 4.69 (5, 1H), 4.43 (I, U - 6.8 Hz, 2H), 3.92 (5, 1H), 3.34 (I, U - 8.4 Hz, 1H), 3.17 (5, 1H), 3.06 (5, 1H ), 2.07 (ad, U - 12.1, 7.5 Hz, 1H), 1.97 (d, U - 6.8 Hz, 2H), 1.62 (y, U - 4.7 Gu, 1OH), 0.67 (aa, U - 13.3, 8.5, 4.2 Hu, 2H), 0.44 (Ida, U - 8.1, 5.0, 3.7 Hz, 4H), 0.37 - 0.29 (t, 1H), 0.20 (ad, U - 6.5, 4.2, 3.6 Hz, 2H), 0.11 (ar , U - 9.7, 4.7 Hz, 2H). MO-IER t/2 calc. 619.29407, found 620.23 (Ma1)k; retention time: 1.94 min. (Method RK 5).

Example 129: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19 ,21-pentaazatetracyclo|18.2.2.111,14.05,10I pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 67) and 12,12-dimethyl-8-(3-12-|1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,21- pentaazatetracyclo| 18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 68)

M Y Gshshe i pr. | ul more ul more sh Shshch zano sho shov slash in dreams rtattriyu

Stage 1: tert-butyl 4-I4-(5-(C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridylamino|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

M ІІІ 5 vVos Mn 5-47 Me 5-4 MA in MU Ten - -і- уй

Vos

In a 20 ml vial, 2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (353.0 mg, 0.9396 mmol) and carbonyldiimidazole (152.4 mg, 0.9396 mmol) was combined in tetrahydrofuran (3.834 mL) and stirred for 120 min at

Then, tert-butyl-2,2-dimethyl-4-(4-(5-sulfamoyl-2-pyridyl)amino|butyl|pyrrolidine-1-carboxylate (267.2 mg, 0, 6264 mmol) in tetrahydrofuran (5.114 mL) followed by the addition of 1,8-diazabicyclo/5.4.0)undec-7-ene (187.4 μL, 1.253 mmol), and the reaction mixture was heated at 50 "C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a shallow gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 4-I4-(5-C2-chloro-6-I3- (2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|2- pyridylamino|butylI|-2,2-dimethylpyrrolidine-i-carboxylate (422.4 mg, 86595 ) as a white solid. MO-IER t/2 calcd. 783.27924, found 784.2 (M--1)x, retention time: 0.86 min (RC Method A).

Stage 2: 2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-3-yl)butylamine|-3-pyridyl|sulfonyl/|-6-(3-(2-

P-«(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide ooo ooo ooo

And KHI

5-47 M si M MN 5-47 M si M MN

M MN

Vos

Tert--butyl-4-I4-C(5-C2-chloro-6-I(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl| 2-Pyridylamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (422.4 mg, 0.5386 mmol) was dissolved in dichloromethane (1.843 mL) and trifluoroacetic acid (1.904 mL, 24.71 mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, treated with sat. without using a solid drying agent).

The organic layer was concentrated on a rotary evaporator followed by drying in vacuo to give 2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-3-yl)butylamine|-3-pyridyl|sulfonyl|-6-( 3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide) (323.6 mg, 88 95) in the form of an off-white solid. MSO-IER t/72 calculations 683.2268, found 684.2 (Ma1)g, retention time: 0.58 min (RC Method A).

Stage 3: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (enantiomer 1) (Compound 67) and 12,12 -dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,19,21- pentaazatetracyclo|18.2. 2.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione

Zo (Enantiomer 2) (Compound 68)

To a solution of 2-chloro-M-((6-(4-(5,5-dimethylpyrrolidin-3-yl)propoxy|-3-pyridyl|sulfonyl|-6-(3-(2-P-"trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (323.6 mg, 0.4730 mmol) in dimethylsulfoxide (12.94 ml) was added potassium carbonate (392.2 mg, 2.838 mmol), cesium fluoride (86 .22 mg, 0.5676 mmol) and a small amount of molecular sieves Z A.

The resulting mixture was closed and heated to 165 "C for 16 hours. Then the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous MNACI and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 422 mg of a yellow-brown amorphous solid substance, which was subjected to chiral NKR chromatography using a SpPigaibak O00-3 column, eluting with isocratic 30 Fo methanol (20 mM MH 3 modifier)/70 95 mobile phase of carbon dioxide for 2 minutes to obtain a single enantiomer of the expected product (first elution, peak 1 ), which still contained some impurities, and another single enantiomer of the expected product (second elution, peak 2), which still contained some impurities as white solids.

The first eluting peak of 1 from the chiral separation of NCR (50.2 mg) was filtered and purified using reverse-phase HPLC-MS using a column

Hypa C18 (2) (75 x 30 mm, particle size 5 μm), sold by Rpepotepeh (рп: 00С-4252-00-

АХ) and a double gradient from 195 to 9995 of mobile phase B for 15.0 min (mobile phase

A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml / min, injection volume - 950 μl and column temperature - 25 "C), which gives 12,12-dimethyl-8- (3-2-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23) ,5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 1) (compound 67) (27.7 mg, 18 95) as a white solid. 1H NMR (400 MHz,

DdMSO-ab) b 12.15 (5, 1H), 8.47 (5, 1H), 8.19 (y, 9 - 2.7 Hu, 1H), 7.81 (a, y - 8.3 Hz, 1H), 7.30 (5, 1H), 6.89 (a, U - 8.3 Hz, 1H), 6.56 (a, U - 8.9 Hz, 1H), 6.10 (a, U - 2.7 Gu, 1H), 4.31 (Her, U - 7.0 Hz, 2H), 2.45 ( 5.1), 2.07 (Her, U - 7.1 Hu, ZN), 1.99 (5, 1H), 1.72 (5, 1H), 1.54 (5, 10H), 1.25 (a, U - 9.7 Hz, 2H), 1.05 (5, 2H), 0.99 - 0.92 (t, 2H), 0.92 - 0.84 (t, 2H). MO-IER t/2 calc. 647.2502, found 648.2 (MA) k; retention time: 2.12 min. (Method of RH B).

The second eluting peak 2 from the chiral separation of NCR (46.5 mg) was filtered and purified by reversed-phase HPLC-MS using an Ipa C18 column (2) (75 x 30 mm, 5 μm particle size) sold by Rpepotepeh (рп: 000-4252-00-АЧ) and a double gradient from 195 to 9995 of mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml /min, the injection volume is 950 μl and the column temperature is 25 "C), which gives 12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole -1-yl)-2А6б-thia-3,9,11,19,21- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24), 21- hexane-2,2,4-trione (enantiomer 2) (compound 68) (29.4 mg, 1995) as a white solid 1H NMR (400 MHz,

DdMSO-ab) b 12.15 (5, 1H), 8.46 (5, 1H), 8.19 (j, U - 2.8 Hz, 1H), 7.60 (a, U - 8.5 Hz, 1H), 7.28 (5, 1H), 6.88 (a, U - 8.3 Hz, 1H), 6.55 (a, U - 8.9 Hz, 1H), 6.10 (a, U - 2.7 Gu, 1H), 4.31 (1, 7 - 7.0 Hz, 2H), 2.07 ( 9 - 7.1 Gu, ZN), 1.99 (5, 1H), 1.72 (y, U - 10.9 Hz, 1H), 1.54 (a, 9 - 1.3 Hz, TON), 1.29 - 1.14 (t, 2H), 1.04 ( 5, 2H), 0.97 - 0.94 (t, 2H), 0.91 - 0.86 (t, 2H). MO-IER t/ calc. 647.2502, found 648.2 (M--T) k; retention time: 2.11 min. (Method of RH B).

Example 130: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2Ab6-thia-3,9 . Compound 69) 9 B -Z --x on Nam | 7 Hebrews 1

M. | - schi M. iy o -- o y M M SI o Vosm un-t a - o oi r 5-47 MU oyi --X Zier2 y / I r: zh Kk - S An g

Coo)

Stage 1: tert-butyl 4-(2-C6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate (9) КЯ О оо

DE M

. that | 2-Chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (154 mg, 0.4099 mmol) and carbonyldiimidazole (66 mg, 0.4070 mmol) were combined in tetrahydrofuran (2.0 mL) and stirred for 90 min at 50 °C. Then tert-butyl-

2,2-dimethyl-4-(2-(b-sulfamoyl-2-pyridyl)amino|ethoxy|pyrrolidine-1-carboxylate (94 mg, 0.2268 mmol) and then 1,8-diazabicyclo|5.4.F )undec-7-ene (85.0 μl, 0.5684 mmol), and the reaction mixture was heated at 50 °C for 36 h. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by brine. Organic layers separated, dried over sodium sulfate, filtered and evaporated, and then purified by reverse-phase preparative chromatography using a C 18 column (30-99 95 acetonitrile in water (5 mM hydrochloric acid) to obtain tert-butyl 4-( 2-I|(6- (2g-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|2-pyridylamino|ethoxy|-2 ,2-dimethylpyrrolidine-1-carboxylate (77 mg, 44 95).

MO-0ER t/» calc. 771.24286, found 772.2 (M--1)k; Holding time: 2.28 min. (Method of RH E).

Stage 2: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo|17.3.1.111,14.05,10)hetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (Compound 69 ) poh OO oo oh vi xx r m | - and iv | In and | y -4 M si o Y-k 2 M y r sh- MH - pod i- o code tert-Butyl 4-(2-C(b6-C2g-chloro-6-I3-(2-/1-"trifluoromethyl )cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|ethoxy|-2,2-dimethylpyrrolidine-1-carboxylate (77 mg, 0.09971 mmol) was dissolved in dichloromethane (1 .6 ml) and hydrochloric acid (800 μl 4 M in dioxane, 3.200 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2 M carbonate was added of sodium (5 ml), obtaining pH - 10.

The organic layer was extracted with ethyl acetate (2 x 10 ml), washed with saline, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The resulting material of potassium carbonate (72 mg, 0.5210 mmol), cesium fluoride (25.0 mg, 0.1646 mmol), molecular sieves ZA and dimethyl sulfoxide (1.6 mL) was combined in a vial purged with nitrogen. covered with a lid, heated to 150"C and stirred for 20 hours.

It was cooled to room temperature, filtered and then purified by reverse-phase preparative chromatography using a C18 column (30-99 95 acetonitrile in water (5 mM hydrochloric acid) to obtain 12,12-dimethyl-8- (3- -2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2A6b-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111,14.05 ,10|hetracose-1(22),5(10),6,68,19(23),20-hexane-2,2,4-trione (compound 69) (38.8 mg, 61 95). IN NMR (400 MHz, DMSO-ab) 5 12.59 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 7.80 (a, 9 - 8.2 Hu, 1H), 7.59 (ad, 9 - 8.5, 7.3 Hz, 1H), 7.13 (a, 9. - 7.7 Hz, 1), 7.10 (a, 9 - 7.0 Hz, 1H), 6.94 (y, 9 - 8.2 Hz, 1H), 6.71 (a, y - 8.2 Hz, 1H), 6.11 (y, U - 2.7 Hz, 1H), 4.31 (1, U - 7.0 Hz, 2H), 4.11 (9, U - 12.68, 5.9 Hz, 2H), 3.88 (I, 9 - 11.6 Gu, 1H), 3.61 (aa, y - 8.7, 4.2 Hz, 1H), 3.32 - 3.20 (t, 1H), 3.06 (ai, U - 10.6, 5.0 Hz, 1H), 2.92 - 2.77 (t, 1H) . 2H). MO-IER t/: calc. 635.21375, found 636.2 (M.-1) k; Holding time: 2.0 min. (Method of RH E).

Example 131: Preparation of 21,21,23-trimethyl-4-(3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9, 13,14-pentaazatetracycloi|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (compound 76) and 12,21,21-trimethyl -4-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracycloyl 17.2.1. 111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (Compound 71)

o oh OM -- M si MN (9) y Kk --- (c) B (9) oy y S Ya ta s x -iZ | ru with M | ru and re, vivr2 o dom M si i o photo M SI zh y Kk - -7 scha

Vos

VosM tihiige og hedioizotegv

Y B Y M y mach y M X 0 M si y o-- TM M si - - khn -7 - -7 o nm

МН тихиге оггедиоизотегв 19) B (c) ох р ЯЗ х M t M ЧЕ' m и B -/ | / (c) M e- -e- sh--

Stage 1: tert-butyl 4-(4-(4-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|- 3Z-methylpyrazol-1-yl|butyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl 4-I4-(A-((2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl |ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|-5-methylpyrazol-1-yl|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) Eight -U M si Me (9) e- sh-

І B ІІІ B sh M ke 5 M і Be -U we si te M | - g 0-37 and 0-7 M si - 5 D('

2-chloro-M-Co-methyl-1H-pyrazol-4-yl)usulfonyl|-6-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1- il|Ipyridine-3-carboxamide (454 mg, 0.8749 mmol),

M,.M-dimethylformamide (4 ml) and potassium carbonate (424 mg, 3.068 mmol). The reaction mixture was stirred for 5 minutes at room temperature, and then tert-butyl-2,2-dimethyl-4-

(4-methylsulfonyloxybutyl)pyrrolidine-i-carboxylate (410 mg, 1.173 mmol) in MM-dimethylformamide (2 mL) was added dropwise. The reaction mixture was placed in an oil bath at 80 C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (gradient 10-99 95 acetonitrile/water modified with 0.1 95 hydrochloric acid, obtaining tert-butyl-4-(4-I4-C(2-chloro-6 -I3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-3-methylpyrazol-1-yl|butyl|-2,2-dimethylpyrrolidine-1- carboxylate and tert-butyl 4-I4-(A-(e-chloro-6-|3- (2-P-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-5 - methylpyrazol-1-yl|Ibutyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (184.3 mg, 27 95). MO-IER t/ cal. 771.27924, found 772.7 (M -a1)g; retention time: 1.85 min. (Method

РХ 5).

Stage 2: 2-chloro-M-(1-I(4-(5,5-dimethylpyrrolidin-3-yl)/butyl|-3-methylpyrazol-4-yl|Isulfonyl-b-

13-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide and 2-chloro-M-(1-(4-(5,5-dimethylpyrrolidin-3-yl)butyl) |-o-methyl-pyrazol-4-yl|sulfonyl-6-I3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (mixture of regioisomers) o o o o o o o ray r 5-47 Mo Sho t 5-47 M s K 5 -e- sh

Vos

Vos tihiige oi gedioivoteg5 (c) Ba (c) and 5-47 Mb ho What; And 5-47 MA toi K and shcha ge 7 days

Mn

Tert-butyl-4-(4-I4-(e-chloro-6-I3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl| -3-methylpyrazol-1-yl|butyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl 4-I4-(A-(e-chloro-6-|3- (2-P-"trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|Ibutyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (81 mg, 0.1049 mmol), dichloromethane (3 mL) and trifluoroacetic acid (450 μL, 5.841 mmol). The reaction mixture was stirred at room temperature for 90 min. The reaction mixture was evaporated.

The residue was washed with 2 M potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-M-HP1-(4-(5,5-dimethylpyrrolidin-3-yl)/butyl|-3-methylpyrazol-4-yl|sulfonyl-b -|(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide and 2-chloro-M-(1-(4-(5,5- dimethylpyrrolidine-3 -yl)/butyl|-5-methylpyrazol-4-yl|sulfonyl-b-|3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (mixture of regioisomers) ( 70

From mg, 99,965). MO-IER t/: calc. 671.2268, found 672.2 (M'n1)x; retention time: 1.64 min. (Way

RK B).

Stage 3: 21,21,23-trimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,13,14-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (compound 76) and 12,21,21 -trimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|vethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14-pentaazatetracyclo|1 7.2.1.111 ,14.02,7|gricose-2,4,6,11(23),12- pentane-8,10,10-trione (Compound 71)

HER 54 HER M 5-47 Me y, Y 5-47 MA oi X 5- 5-7 -- nm

Mn tihiige oi gedioivote g

Y 54 Y B 5-7 - what

To /2-chloro-M-P1-(4-(5,5-dimethylpyrrolidin-3-yl)butyl|-3-methylpyrazol-4-yl|sulfonyl-6-(3-(2-

P-«(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide and 2-chloro-M-(1-(4-(5,5- dimethylpyrrolidin-3-yl)/butyl|-5 -methylpyrazol-4-yl|sulfonyl-b-|(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (mixture of regioisomers)) (70 mg, 0.1041 mmol) were added potassium carbonate (72 mg, 0.5210 mmol), cesium fluoride (36 mg, 0.2370 mmol) and dimethyl sulfoxide (800 μl). The reaction was heated at 150 °C overnight.

The reaction mixture was cooled to room temperature, filtered and purified using

HPLC (20-80 95 acetonitrile in water with a modifier of 0.190 hydrochloric acid), obtaining as the first eluted peak 12,21,21-trimethyl-4-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1 N-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracyclo!y17.2.1.111,14.02,7|gricose-2,4,6,11(23),12- pentane-8,10,10-trione (compound 71) (16.6 mg, 50 95); IN NMR (400 MHz, DMSO-ab) b 12.25 (5, 1H), 8.63 (5, 1H), 8.21 ( ai, U - 4.5, 2.8 Hu, 1H), 7.85 - 7.74 (t, 1H), 6.92 (aa, U - 8.3, 4.4 Hz, 1H), 6.11 (ai, U - 2.7, 1.5 Hu, 1H), 4.31 (d, y - 6.4, 5.9 Hz, ЗН), 4.10 (а, У - 11.9, 6.8 Hz, 1Н), 2.85 (I, У - 10.1 Hz, 1Н), 2.67 (65, 1Н), 2.39 (5, ЗН), 2.15 - 2.02 (t, 4Н), 1.83 (аа, У - 11.6, 5.6 Hz, 1Н), 1.58 (а, у - 6.7 Hz, 4Н), 1.51 (y, 9 - 5.9 Hz, 5Н), 1.19 (a,

In 8.8 Hz, 2H), 1.02 - 0.93 (t, 2H), 0.93 - 0.85 (t, 2H), 0.13 (5, 1H), MO-IER t/: cal. 635.2502, found 636.4 (M--1)k; Holding time: 2.14 min. (Method of RH B) apa az She 5esopa reaction o eishe, 21,21,23-Piteiyu!-4-(3-12-11-iyogoteiNu!)susiorgoruCetohu)-1 H-ruga?o01-1-il)-10X6 -thia- 1,3,9,13,14-pentaazatetracyclo!17.2.1.111,14.02,7|hysose-2,4,6,11(23),12-repiacepe-8,10,10-trione (Compound 76 ) (4.2 mg, 13,950); MOS-IER t/2 calc. 635.2502, found 636.3 (Ma1)-; Retention time: 2.08 min (method RH B).

Example 132: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2Ab6-thia-3,9 . enantiomer 1) (Compound 74) and 12,12-dimethyl-8-(3-(2-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11,18,23- pentaazatetracycloyl 1 7.3.1.111,14.05,10) tetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 75)

KOM I OM pnia zaao nz rod y kp vod Sl y vya -A oh Sk v -A S an

Zo Stage 1: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo|17.3.1.111,14.05,10)hetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (enantiomer 1 ) (Compound 74) and 12,12-dimethyl-8-(3-(2-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2A6-thia-3,9,11,18,23- pentaazatetracyclo!yl17.3.1.111,14.05,10| hetracose-1(22),5(10),6,68,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 75)

KOM PO AND U

U m hu hu THAT hu! y s y y

M. this is M I -- M more M I and uko M m --Shciaa o M M M o o to M M o o o dl da dp Dn pl Water!

Racemic 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa-2Abthia-3,9,11,18 ,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(22),5(10),6,8,19(23),20-hexane-2,2,4-trione (36 mg 0 .05607 mmol) to chiral separation by NCR chromatography using SpPigaIRak A5-H (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase gradient from 5 95 to 60 95 methanol (20 mM MNH) in carbon dioxide at 50 ml/min with obtaining as the first eluted enantiomer 12,12-dimethyl-8-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15-oxa- 2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)tetracose-1(22),5(10),6,8,19(23),20-hexane -2,2,4-trione (enantiomer 1) (compound 74) (9.76 mg, 54 95) as an off-white solid; MO-IER tp/2 calc. 635.21375, found 636.2 (M-- 1); Retention time: 2.0 min. -15-oxa-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|tetracose- 1(22),5(10),6,8,19(23), 20-hexane-2,2,4-trione (enantiomer 2) (compound 75) (11.29 mg, 63 90) as an off-white solid; MO-IER t/2 calc. 635.21375, found 636.2 (М-А1) k;

Retention time: 2.0 min (RC method).

Example 133: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,23 -tetraazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (Compound 78)

M KY o mm nat te nal chi hi . still Vivr1 no TO ovivr? 7 And ru u. VierZ -- - - --- -- M ro -- --I

M 2 M o U M si

Vg VosMm | | і- -A vk ish ish y m z y m z m. | - y I ro Bier4 M | ru n Y ro shrpU M si -shschOo- M M v

Stage 1: tert-butyl 2,2-dimethyl-4-I(4-(6-sulfamoyl-2-pyridyl)but-Z-ynyl|Ipyrrolidine-1-carboxylate (c)

M

(in)

M JSC | 7

VosM | | zhk nt | y: M ih -- me

Vg VosM

b-Bromopyridine-2-sulfonamide (840 mg, 3.543 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (125 mg, 0.1781 mmol) and copper iodide (34 mg, 0.1785 mmol) were sequentially added to a round-bottomed flask. ). Then, anhydrous M,M-dimethylformamide (11 ml) was added to the vessel, sealed with a rubber septum in a nitrogen atmosphere, followed by the addition of diisopropylamine (1000 μl, 7.135 mmol). Then tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (1.15 g, 4.575 mmol) in 3 ml of N,M-dimethylformamide was added and

The reaction mixture was heated to 100 °C in an oil bath in a nitrogen atmosphere for 2 hours.

The residue was diluted with ethyl acetate and washed with water (2 x 50 ml), then with saline (50 ml). The organic layers were combined, dried (sodium sulfate), filtered, and concentrated to an orange residue, which was purified by chromatography on silica gel using a gradient of 100 90 hexanes to 90 905 ethyl acetate in hexane to give tert-butyl- 2,2-Dimethyl-4-(4-(6-sulfamoyl-2-pyridyl)but-3-ynyl|Ipyrrolidine-1-carboxylate (1.4 g, 97,956). NMR (400 MHz, DMSO-ab ) b 8.04 (I, U - 7.8 Hz, 1H), 7.85 (ai, U - 7.9, 0.8 Hz, 1H), 7.67 (ad, 9 - 7.7, 3.5 Hz, 1H), 7.53 (5, 2H), 3.63 (yes, U - 18.0, 9.0 Hz, 1H), 2.88 (d, U - 10.5 Hz, 1H), 2.58 - 2.52 (t, 1H), 2.24 (5, 1H), 1.94 (yes, 9 - 20.1, 6.4 Hz, 1H), 1.64 (ai, U - 14.1, 7.0 Hz, 2H), 1.50 (aa, U -22.0, 9.7 Hz, 1H), 1.39 (da, U - 18.3, 9.6 Hz, 13H), 1.26 (5 , ZN). MO-IER t/2 calculated 407.18787, found 408.2 (M.-1) k, retention time: 1.77 min (Method RH E).

Stage 2: tert-butyl 2,2-dimethyl-4-I4-(6-sulfamoyl-2-pyridyl)butyl|pyrrolidine-1-carboxylate

M M nd ek nat y:

M. 2 M y

VosM

M

/

Vos

Platinum oxide ( 61.29 mg, 0.2699 mmol) then methanol (11.00 mL) and the mixture was purged with nitrogen, then hydrogen, then closed with a hydrogen balloon and stirred for 4 hours. Additional platinum oxide (61.29 mg, 0.2699 mmol) was added ) and stirred for 1 h. The reaction mixture was filtered through celite and washed with excess methanol, and then the filtrate was concentrated. The residue was then purified by silica gel chromatography using a gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl- 2,2-dimethyl-4-N4-(6-sulfamoyl-2-pyridyl)butyl|pyrrolidine-1-carboxylate (1.10 g, 99 95), which was contaminated with a small amount of intermediate olefin and was used directly in the next step. MO-IER t/2 calculated 411.21918, found 412.2 (M-AT) w Retention time: 1.85 min (Method RH E).

Stage 3: tert-butyl 4-I(4-(6-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl| -2-pyridyl|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate mm p se M ra: U xx I 5 pom | 5 on | y

M x 0-th wk M Go p

Es

M that in 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (685 mg, 1.823 mmol) and carbonyldiimidazole (296 mg, 1.825 mmol) were combined in tetrahydrofuran (11 ml) and stirred for 90 min at 50 "C. Then tert-butyl-2,2-dimethyl-4-(4-(6-sulfamoyl-2-pyridyl)butyl|pyrrolidine was added -1-carboxylate (500 mg, 1.215 mmol),

Zo and then 1,8-diazabicyclo(/5.4.F)undec-7-ene (455 μL, 3.043 mmol), and the reaction mixture was heated at 50 °C for 18 h. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 75 95 ethyl acetate in hexane to give an off-white solid, third -butyl 4-I4-I6-Ce-chloro-6-I3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylbutyl|-2, 2-Dimethylpyrrolidine-i-carboxylate (165 mg, 35 95). MO-IER t/2 calcd. 768.2684, found 769.2 (M--1) k; retention time: 2.13 min. (RC method 0).

Stage 4: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,23-tetraazatetracyclo| 17.3.1.111,14.05,10|htetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (Compound 78)

oh oh

M o o o

In Mosulov o uk 4 si She M. r M i - -- zh -tt t n» zna FI M M se

M os

tert-butyl 4-I4-(I6-C(2-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridyl butyl|-2,2-dimethylpyrrolidine-1-carboxylate (125 mg, 0.1625 mmol) was dissolved in dichloromethane (2.5 mL) and hydrochloric acid (1.5 mL of 4 M in dioxane, 6.000 mmol) was added to the mixture. and stirred at room temperature for 30 min.

The mixture was concentrated to dryness under reduced pressure and combined with potassium carbonate (135 mg, 0.9768 mmol), cesium fluoride (40 mg, 0.2633 mmol), 3 A molecular sieves, and dimethyl sulfoxide (2.5 mL) in a vial, purged with nitrogen, the vial was closed, heated to 15072 and stirred for 20 hours. It was cooled to room temperature, and the mixture was filtered, and then purified by reversed-phase preparative chromatography using a C18 column (30-99 Fo acetonitrile in water (5 mM hydrochloric acid) to give 12,12-dimethyl-8- (3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,23-tetraazatetracyclo|17.3.1.111,14.05,10|hetracose - 1(23),5,7,9,19,21-hexane-2,2,4-trione (Compound 78) (37.67 mg, 37 90). MO-IER t/2 cal. 632.23926 , found 633.2 (M.-1)xk, retention time: 1.92 min (method RH b).

Example 134: Preparation of 21,21,23-trimethyl-4-(3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10Abthia-1,3,9,13, 14-pentaazatetracyclo!17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (Compound 80) and 21,21,23 -trimethyl-4-(3-12-|(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6bthia-1,3,9,13,14- pentaazatetracycloyl 17.2.1. 111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 81)

KOM Y M s Y U pt ro still -Kschen vv

Stage 1: 21,21,23-trimethyl-4 (3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6bthia-1,3,9,13, 14-pentaazatetracycloi17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (Compound 80) and 21,21,23 -trimethyl-4-(3-12-11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6bthia-1,3,9,13,14- pentaazatetracyclo!|17.2.1.111,14.02 ,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 81) M. m M m m vv " oo dp vody dep o

Zo 21,21,23-trimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14- pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (12 mg, 0.01888 mmol) was subjected to chiral separation using NKR -chromatography using SpigaIRak A5-H (column 250 x 21 mm, particle size 5 μm) with a mobile phase of 20-25 95 methanol (20 mM MNH) in carbon dioxide at 50 ml/min (injection volume - 950 μl 4 mg/ml solution in 50 95 methanol in dimethyl sulfoxide) with obtaining 21,21,23-trimethyl-4 (3-12-11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl as the first eluted enantiomer )-10A6-thia-1,3,9,13,14-pentaazatetracyclo|1 7.2.1.111,14.02,7|gricose-2,4,6,11(23),12- pentane-8,10,10- trione (enantiomer 1) (compound 80) (3.3 mg, 55 95); MO-IER t/: calc. 635.2502, found 636.3 (M. 1); Retention time: 2.95 min (LC method 0) and as the second eluted enantiomer 21,21,23-trimethyl-4-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole-1 -yl)- 10X6-thia-1,3,9,13,14-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-

8,10,10-trione (enantiomer 2) (compound 81) (3.8 mg, 63 90); MO-IER t/2 calc. 635.2502, found 636.3 (M. 1); Retention time: 2.95 min (method РХ 0).

Example 135: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,23 -tetraazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 86) and 12,12- dimethyl-8-(3-12-(11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,23- tetraazatetracyclo!|17.3.1.111,14.05 ,10|tetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 87)

TO THEIR HOUSE

He uh Z u z He Z o

M - Mo Ver M 24 She ya le r ay sa

Stage 1: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,23-tetraazatetracyclo| 17.3.1.111,14.05,10|htetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 86) and 12,12-dimethyl-8 -(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,23- tetraazatetracyclo!|17.3.1.111,14.05,1d Hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (enantiomer 2) (Compound 87)

Racemic 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,23-tetraazatetracyclo |17.3.1.111,14.05,10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (34.9 mg, 0.05516 mmol) to chiral separation using NKR-chromatography using Spiga! Rak A5B-H (250 X 10 mm column, particle size 5 μm) with a mobile phase of 25 95 acetonitrile:methanol (90:10; without modifier), 75 95 carbon dioxide at 10 ml/min (injection volume - 70 μl - 24 mg/ml in a mixture of acetonitrile:methanol (90:10)) with obtaining as the first eluted enantiomer 12,12-dimethyl-8-(3-12-I1-«"trifluoromethyl)cyclopropyl|ethoxy)-1 H- pyrazol-1-yl)-2A6-thia-3,9,11,23-tetraazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5,7,9,19,21-hexane-2 ,2,4-trione (enantiomer 1) (compound 86) (13.11 mg, 74,905) as a white solid; 1H NMR (400 MHz,

DMSO-ab) b 12.74 (5, 1H), 8.21 (a, 9U - 2.7 Hu, 1H), 8.08 (1, 9 - 7.7 Hu, 1H), 8.01 (a, U - 7.6 Hz, 1H), 7.18 ( a, 9 - 7.6 Gu, 1H), 7.64 (a, y - 7.6 Hz, 1H), 6.92 (y, U - 8.2 Hz, 1H), 6.12 (0, U - 2.7 Hz, 1H), 4.32 (9 - 7.0 Hz, 2H), 2.87 (5, 2H), 2.84 - 2.77 (t, 1H), 2.67 (y, U - 12.6 Hz, 1H), 2.16 (da, 9 - 11.5, 5.3

Zo Hz, 1H), 2.08 (her, U - 7.0 Hz, 2H), 1.98 - 1.85 (t, 2H), 1.61 (5, 1H), 1.53 (Her, U - 24.3 Hz, 8H), 1.45 (5, 1H), 1.03 (yes, U - 12.9, 7.3 Hz, 1H), 0.96 (I, U - 5.7 Hz, 2H), 0.92 (a, U - 8.6 Hz, 1H), 0.89 (5, 2H), MO-

IER t/72 calc. 632.23926, found 633.2 (MAT); Holding time: 1.88 min. (Method of RH c) apa az She zesopa epapiotegio eIshe, 12,12-dimethyl-8-(3-12-11-(iiogoteiNui)susiorgorui|eshohu)-1H-ruga201-1-yl)-2A6-thia- 3,9,11,23-і1еігагаівігасусіо |(17.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (epapioteg 2) ( Compound 87) (12.96 mg, 74 90) az a m/pye zoiiy; MO-IER t/: calc. 632.23926, found 633.2 (M--1)k; Holding time: 1.92 min. (Method РХ 0).

Example 136: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab-thia-3,9 ,11,20-tetraazatetracycloi|17.2.2.111,14.05,10|hetracose-1(21),5(10),6,8,19,22-hexane-2,2,4-trione (Compound 90)

oh oh

M t on on KU nd CHO sh | Veeya in -8 Ex Vier1 - em M si

VosM Y Sh pf ; " І І я-( А " Ш VosM ts

IM Om g p y BVierz M - ru zh V ut I driver

B I 7

Stage 1: tert-butyl 2,2-dimethyl-4-I3-(5-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate

M on M nt Fe i nt y: - shay M (c)

VosmM -

M si i

Man ( 125 mg, 3.125 mmol) (CAUTION: evolution of gas) and the mixture was stirred at room temperature for 20 minutes. b-Chloropyridine-3-sulfonamide (296 mg, 1.537 mmol) was then added and the resulting mixture was stirred at room temperature for 140 minutes, then Mann (62 mg, 1.550 mmol) was added (CAUTION: evolution of gas) and the resulting mixture was heated to 100 C after installing a reflux condenser for 20 hours. b-Chloropyridine-3-sulfonamide (145 mg, 0.750 mmol, Mann (62 mg, 1.55 mmol)) was added and heated to 105 C for 20 hours. Then the mixture was poured into 1 n .citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered, and concentrated to a yellow oil which was purified by chromatography on silica gel using a gradient of 100 95 hexanes to 65 95 ethyl acetate in hexane to give a third -butyl-2,2-dimethyl-4-N3-(5-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate (50.36 mg, 8 95).

MO-ER t/2 calc. 413.19846, found 414.2 (M--1); Holding time: 1.81 min. (Method of RH E).

Stage 2: tert-butyl 4-I3-(5-(C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|oxy|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Oo oo

M ge) r nm xx | and | 7y - and | sch memes si Mo

M (o) in --- / o -4 ZM ho -K A

VosM d-Es Vosm c 2-Chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (69 mg, 0.1836 mmol) and carbonyldiimidazole (30 mg, 0.1850 mmol) was combined in tetrahydrofuran (1.108 mL) and stirred for 90 min at room temperature. pyridyl)oxy|propyl|pyrrolidine-1-carboxylate (50.36 mg, 0.1218 mmol) followed by 1,8 diazabicyclo(/5.4.0)undec-7-ene (50 μl, 0.3343 mmol), and the reaction mixture was heated for 18 hours at 50 C. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution and then with brine.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated,

Z was then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexane to give tert-butyl-4-

IZ-KF5-Ce-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridyl|oxy|propyl|-2, 2-dimethylpyrrolidine-1-carboxylate (71 mg, 76 95).

MO-ER t/2 calc. 770.2476, found 771.2 (M--1)k; Holding time: 2.11 min. (Method of RH E).

Stage 3: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11 ,20-tetraazatetracyclo!|17.2.2.111,14.05,10|hetracose-1(21),5(10),6,8,19,22- hexane-2,2,4-trione (Compound 90) (4 MORE

M kh - p o UM M si M o ul m M o - (o) p a hod 7 - y from all

tert-butyl 4-I3-C5-C2-chloro-6-I3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridyl|oxy |propyl|-2,2-dimethylpyrrolidine-1-carboxylate (71 mg, 0.09206 mmol) was dissolved in dichloromethane (1.5 mL) and hydrochloric acid (4M in dioxane) was added to the mixture (800 μL of 4 M, 3.200 mmol ), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2 M sodium carbonate (5 ml) was added, obtaining pH - 10. The organic layer was extracted with ethyl acetate (2 x 10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The obtained material and potassium carbonate (69 mg, 0.4993 mmol), cesium fluoride (23 mg, 0.1514 mmol), molecular sieves Z A and dimethyl sulfoxide (1.5 ml) were combined in a vial, purged with nitrogen, closed with a lid , heated to 155"C and stirred for 24 hours.

It was cooled to room temperature, filtered, and then purified by reverse-phase preparative chromatography using a C 18 column (30-99 95 acetonitrile in water (5 mM hydrochloric acid) to obtain 12,12-dimethyl-8- (3-12-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2A6-thia-3,9,11,20-tetraazatetracycloi|17.2.2,111,14, 05,10|hetracose-1(21),5(10),6,8,19,22-hexane-2,2,4-trione (compound 90) (3.95 mg, 7 96). MO-IER t/2 calcd 634.2185, found 635.2 (M-a-1); Retention time: 2.27 min (Method RH E).

Example 137: Preparation of 12,21,21-trimethyl-4-(3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-106-thia-1,3,9, 13,14-pentaazatetracycloi!17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (compound 91) and 12,21 ,21-trimethyl-4-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14-

From pentaazatetracyclo!y17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 92) (o) oo Y M. Y. M

M. | 2 and ra; - Veot other but av zm and zhk Mch M da rota that Ua ro

Stage 1: 12,21,21-trimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,13,14-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (compound 91) and 12 ,21,21-trimethyl-4-(3-12-|(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 92)

Racemic 12,21,21-trimethyl-4-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14 -pentaazatetracyclo!|17.2.1.111,14.02,7|tricose-2,4,6,11(23),12-pentane-8,10,10-trione (35 mg, 0.05506 mmol) was subjected to chiral separation by NKR chromatography using a SPigai Rak AB-N column (250 X 10 mm, particle size 5 μm) with 20-30 95 methanol (20 mM MNH) in the mobile phase of carbon dioxide, giving 12,21,21-trimethyl as the first eluted enantiomer -4-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14-pentaazatetracyclo!|17.2.1.111, 14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (compound 91) (12.1 mg, 69 95); MO-IER t/2 calc. 635.2502, found 636.3 (M--1)4; Retention time: 3.04 min (LC method 0) and as the second eluted enantiomer 12,21,21-trimethyl-4-(3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazole-1 -il)-

10X6-thia-1,3,9,13,14-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione ( enantiomer 2) (compound 92) (8.9 mg, 51 95); MO-IER t/2 calc. 635.2502, found 636.3 (M'-1); Retention time: 3.03 min (RC method).

Example 138: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11,18 ,20-pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 93)

M o nt | y 2 ra x tm M si si r: Mn ya-K i

Vos school 1 st

MM M si y" V Mn MM M y" -K MN -( And water! 7 s u

Vos

Stage 1: tert-butyl 2,2-dimethyl-4-3-K4-sulfamoyl-2-pyridyl)amino|Ipropyl|pyrrolidine-1-carboxylate

KU Sun | Eh

VosMm XX Sai

MN. same -- - in a 4 »: and Mn o o

M

/

Vos

A solution of 2-chloropyridine-4-sulfonamide (300 mg, 1.557 mmol), tert-butyl-4-(33-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (399.2 mg, 1.557 mmol),

Sodium tert-butoxide (224.4 mg, 2.335 mmol) and chlorine (2-di-tert-butylphosphino-2'4",6'-tri-isopropyl-1,1"-biphenyl)|(2-(2-aminoethyl )phenyl|palladium(I) (202.8 mg, 0.3114 mmol) in dioxane (5.000 mL) was degassed by nitrogen purging, and the mixture was stirred at room temperature for 2 hours.The reaction mixture was diluted with ethyl acetate and washed with brine.

The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.

The resulting brown residue was purified by silica gel column chromatography using a gradient of 100 95 dichloromethane to 20 95 methanol in dichloromethane to give tert-butyl-2,2-dimethyl-4-(3-(4-sulfamoyl-2-pyridyl)amino |propyl|pyrrolidine-1-carboxylate (175 mg, 27 95, mixture 1:11 with tert-butyl-4-3-bis(4-sulfamoyl-2-pyridyl)amino|Ipropyl|-2,2-dimethylpyrrolidine-1 -carboxylate) in the form of a light brown sticky solid, which was used directly in the next stage. MSO-IER tp/2 calcd. 412.21442, found 413.6 (M.-1)xk; retention time: 0.5 min (Method of RH A).

Stage 2: tert-butyl 4-I3-C4-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate chu (9) пе 5 І І У

Мн я М М s -6-- o uk M si " z яЯ-( 7 -A che 7 ge

Vos /

Bos 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (154.8 mg, 0.4120 mmol) and carbonyldiimidazole (66, 81 mg, 0.4120 mmol) were combined in tetrahydrofuran (2.0 ml) and stirred for 90 min at 50 "C. Then tert-butyl-2,2-dimethyl-4-13-(4-sulfamoyl- 2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (85 mg, 0.2060 mmol) followed by 1,8-diazabicyclo/5.4.0)undec-7-ene (47.04 mg, 46.21 μl , 0.3090 mmol), and the reaction mixture was heated at 50 "С for 18 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride solution, followed by washing with saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated.

The resulting brown residue was purified by reversed-phase HPLC-MS using a double gradient from 20 95 to 99 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "C) with obtaining tert-butyl-4-3-((4-(2-chloro-6-I3-(2-P1-( trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3- carbonyl|Isulfamoyl|-2-pyridylIamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (45.6 mg, 29

Pho ) in the form of an off-white solid. 1H NMR (400 MHz, Spiogotogt-a) b 8.33 - 8.28 (t, 1H), 8.28 - 8.12 (t, 2H), 7.70 (aa, U - 8.2, 4.3 Hz, 1H), 7.28 (a, 9U - 6.1 Hz, 1H), 7.21 (a, U - 16.4 Gu, 1H), 5.9541, 9 2 2.7 Hz, 1H), 4.39 (Y, U - 7.1 Hz, 2H), 3.77 - 3.68 (t, 1H), 3.68 - 3.52 (t, 1H), 3.38 (5, 2H), 2.85 (I, U 2 11.7 Hu, 1H), 2.23 - 2.11 (t, 1H), 2.09 (i, U - 7.2 Hu, 2H), 1.94 - 1.79 (t, 1H), 1.75 - 1.56 (t, 2H), 1.43 (5, 12H), 1.35 (5, 2H), 1.26 (5, ЗН), 1.07 - 0.97 (t, 2H), 0.73 (5, 2H ). MO-IER t/27 calc. 769.2636, found 770.4 (М--1); Holding time: 0.77 min. (Method of RH A).

Stage 3: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,20- pentaazatetracyclo|1 7.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 93) o Kf so Ff 14 m | r r; | 7x with | 5

I-0 M SI m ru ry; - MN o- tm M M i

Vos

Solution / tert-butyl-4-I3-C4-C(2g-chloro-6-I(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl| -2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (50 mg, 0.06491 mmol) in dichloromethane (416.7 μL) and trifluoroacetic acid (74.01 mg, 49.67 μL, 0. 6491 mmol) was stirred at room temperature for 4 hours.The solvents were removed

Zo and the residue were dissolved in ethyl acetate. It was washed with 2 ml of a saturated solution of sodium bicarbonate, the organic layer was collected, the solvent was removed, then it was dried in a vacuum. The resulting residue was dissolved in dimethylsulfoxide (2,500 ml), molecular sieves Z A were added, and the reaction mixture was stirred for 10 min. Cesium fluoride (29.58 mg, 0.1947 mmol) and potassium carbonate (26.91 mg, 0.1947 mmol) were then added, and the reaction mixture was heated at 130 °C overnight.

The reaction mixture was filtered through a UUPytap disc filter (Rigadiz 25 TE), and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 20 to 80 95 mobile phase B for 15.0 min (mobile phase A - water (0, 05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain /12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)- 2A6b-thia-3,9,11,18,20- pentaazatetracyclo!i17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2, 2,4-trione (compound 93) (12.3 mg, 30 95) as a light yellow solid. 1H NMR (400

MHz, Spiogoitogit-a) 6 8.39 - 8.22 (t, 1H), 8.16 (5, 1H), 7.94 (5, 2H), 7.61 (5, 1H), 7.20 (5, 1H), 6.98 (5,

1H), 5.91 (5, 1H), 4.37 (5, 2H), 3.47 (y, 9 - 13.7 Hz, 2H), 3.01 (a, U - 43.7 Hz, 2H), 2.20 (5, 1H), 2.08 ( 9 - 7.1 Gu, ЗН), 1.86 (5, 2Н), 1.71 (5, 2Н), 1.65 (5, ЗН), 1.61 (5, ЗН), 1.30 (а, У - 39.7 Hz, 2Н), 1.05 - 0.98 (t, 2H), 0.74 (5, 2H). MO-IER ip/2 calc. 633.2345, found 634.4 (M--1)k; Holding time: 1.75 min. (Method of RH B).

Example 139: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9 ,11,21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 94)

M o i nt OH u. faith

AT 7 - Vos, its Vivr1 M (in it M si t o vola -Z5- that additional

HOUSE ooo t M y M - M si M o vivrz m s is in y to v

Stage 1: tert-butyl 2,2-dimethyl-4-I(4-(5-sulfamoyl-2-pyridyl)oxy|butyl|pyrrolidine-1-carboxylate

B t kh nya Fe and Vos,. "Mo o-ya - - -sh pri - M

M SI

Man (240 mg) was added portionwise to tert-butyl-4-(4-hydroxybutyl)-2,2-dimethylpyrrolidine-1-carboxylate (800 mg, 2.948 mmol) under nitrogen atmosphere in M,M-dimethylformamide (8 mL) under stirring , 6.001 mmol) (CAUTION: evolution of gas) in a 20 mL vial, and the mixture was stirred at room temperature for 20 minutes. Then b-chloropyridine-3-sulfonamide (570 mg, 2.959 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour, then Mann (120 mg, 3.000 mmol) was added (CAUTION: gas evolution), the vial was closed and the resulting mixture was heated to 100 "C for 20 hours. 6-Chloropyridine-3-sulfonamide (145 mg, 0.750 mmol) and Mann (62 mg, 1.55 mmol) were additionally added and heated to 10570 for 48 hours. Then the mixture was poured into 1 n. lemon acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a yellow oil which was purified by chromatography on silica gel using a gradient of 100 95 hexanes to 65 95 ethyl acetate in hexane followed by a second purification on silica gel using a gradient from 100 95 dichloromethane to 15 95 methanol in dichloromethane to obtain tert-butyl-2,2-dimethyl-4-I4-K5-sulfamoyl-2-pyridyl)oxy|butyl|pyrrolidine- 1-carboxylate (335 mg, 27 95). L1H NMR (400 MG ts, DMSOSO-ab) b 8.54 (0.9 - 2.1 Hu, 1H), 8.10 - 7.95 (t, 1H), 7.44 (a, U - 6.2 Hz, 2H), 6.98 (9, U - 8.8 Hz, 1H ), 4.32 (i,

U 6.6 Hz, 2H), 3.55 (aa, 9U - 17.1, 6.9 Hz, 1H), 2.78 (d, U - 10.5 Gu, 1H), 2.19 - 2.01 (t, 1H), 1.95 - 1.80 (t, 1H) , 1.76 - 1.68 (t, 2H), 1.44 (a, U - 12.1 Hz, 2H), 1.40 - 1.36 (t, 12H), 1.32 (a, U - 17.3 Gu,

From ZN), 1.24 (5, ZN). MO-IER t/: calc. 427.21408, found 428.2 (M.-1) k; retention time: 1.87 min. (Method of RH E).

Stage 2: tert-butyl 4-I4-(5-(C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|oxy|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o o o

My communication with the students of Kk | y CHO ru m k z o U M SI M (o) vos M (c) k o di M si - lo- --7 - -

Es

M os. 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (437.0 mg, 1.163 mmol) and carbonyldiimidazole (190.0 mg, 1.172 mmol) were combined in tetrahydrofuran (7.260 ml) and stirred for 90 min at 50 "C. then tert-butyl-2,2-dimethyl-4-14-((5-sulfamoyl-2-pyridyl)oxy) was added. butyl|pyrrolidine-i-carboxylate (330 mg, 0.7718 mmol) followed by 1,8-diazabicyclo/5.4.F3undec-7-ene (322.6 mg, 316.9 μL, 2.119 mmol), and the reaction mixture heated at 50 C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100

Fo hexanes to 55 95 ethyl acetate in hexane followed by a second purification on silica gel using a gradient from 100 95 dichloromethane to 15 95 methanol in dichloromethane to give a light yellow solid, tert-butyl 4-I4-(5-C2-chloro-6 -I3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2- pyridyl|oxy|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 58 95). MO-IER t/2 calcd 784.2633, found 785.2 (M--1) k, retention time: 2.19 min (Method Х 0).

Stage 3: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11, 21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,29(24),21-hexane-2,2,4-trione (Compound 94) o o o

M dO we We m Mo o

And

Vos

tert-butyl 4-(A-C5-C2-chloro-6-I3-(2-11-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl| /2-pyridyl|oxy |butyl|-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 0.4457 mmol) was dissolved in dichloromethane (7.5 mL) and hydrochloric acid (4.0 mL of 4 M in dioxane, 16.00 mmol) and stirred at room temperature for 1 min. The mixture was concentrated to dryness under reduced pressure, re-dissolved in ethyl acetate, and then aqueous 2 M sodium carbonate (5 ml) was added, obtaining pH - 10. Extracted with ethyl acetate (2 x 10 ml), vol. organic layers were combined, washed with saline solution, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The obtained material and potassium carbonate (310 mg, 2.243 mmol), cesium fluoride (105 mg,

Zo 0.6912 mmol), molecular sieves 3 A and dimethylsulfoxide (7.5 ml) in a vial purged with nitrogen, closed with a lid, heated to 150"C and stirred for 20 hours.

It was cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100% hexanes to 55% ethyl acetate in hexane to give 12,12-dimethyl-8.- as an off-white solid. (3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11,21-tetraazatetracyclo|18.2.2.111,14.05,10 |pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 94) (76.3 mg, 26,905). MO-IER, etc./2 calc. 648.2342, found 649.2 (Ma-1)k; Holding time: 2.41 min. (Method of RH E).

Example 140: Preparation of (145)-8-I3-(3,3-dimethylbutyl)-4-methyl-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18 ,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (hydrogen chloride salt) (Compound 97)

o o o t, vivr1 os - -- vivr2 zlotO vir o HER M her KU

MN i s M m M Zier4 k | I k Iv podi podi; - Her

Stage 1: 1-benzyl-4-methylpyrrolidin-2-one o (c) c, o (i -- -3--

4-methylpyrrolidin-2-one (1.52 g, 15.33 mmol) and anhydrous tetrahydrofuran (30 ml) were charged to a 100 ml flask under nitrogen atmosphere. The mixture was cooled in an ice bath and Mann (811.9 mg 60 95 wt., 20.30 mmol) was added in small portions. Significant foaming was noted and the reaction turned into a poorly stirred suspension. Stirring was facilitated by the addition of additional tetrahydrofuran (10 mL). The mixture was stirred in a cooling bath for 1.5 hours. Benzyl bromide (2.2 mL, 18.50 mmol) was added dropwise via syringe. The mixture was stirred in a cooling bath, which was allowed to slowly warm to room temperature overnight. After 29 h, the reaction mixture was poured into ice/water.

The product was extracted with ethyl acetate (2 x 75 ml), the organic phase was dried over sodium sulfate, filtered and the solvents were evaporated. The residue was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of ethyl acetate (0 to 100,905) in hexane to give 1-benzyl-4-methylpyrrolidin-2-one (2.52 g, 87 95) as a light brown oil. 1N

NMR (400 MHz, Spiogotogt-a) b 7.37 - 7.17 (t, 5H), 4.44 (5, 2H), 3.36 (aa, 9 - 9.6, 7.7 Hz, 1H), 2.82 (aa, U - 9.6, 6.0 Hz , 1H), 2.61 (ai, 9 - 16.6, 8.6 Hz, 1H), 2.40 (aa, U - 8.6, 7.8, 6.9, 6.0 Hz, 1H), 2.08 (aa, U - 16.6, 6.9 Hz, 1H), 1.07 (a, U - 6.8 Gu, ZN). MO-IER t/2 calc. 189.11537, found 190.1 (MA1) Kk; Holding time: 1.16 min. (Method of RH B).

Stage 2: 1-benzyl-3-(3,3-dimethylbutyl)-4-methyl-pyrrolidin-2-one (o) (c)

M Vg M we -- yes

A 100 mL round bottom flask was dried using a heat gun under vacuum and filled with nitrogen. A flask was charged with 1-benzyl-4-methylpyrrolidin-2-one (542 mg, 2.864 mmol) and anhydrous tetrahydrofuran (8 mL). After cooling to -78 "C, a solution of n-butyllithium (1.3 ml, 2.5 M in hexane, 3.250 mmol) was added dropwise, causing the formation of a red solution. After stirring at -78 "C for 30 minutes, 1 -bromo-3,3-dimethylbutane (450 μl, 3.195 mmol). The mixture was stirred in a cooling bath, which was then allowed to slowly warm to room temperature. After 22 h, the mixture was quenched by adding saturated aqueous ammonium chloride (50 ml). The product was extracted with ethyl acetate (3 x 20 ml), and

The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in oil. Column chromatography on silica gel using a gradient of 0 90 to 40 95 ethyl acetate in hexane gave 1-benzyl-3-(3,3-dimethylbutyl)-4-methylpyrrolidin-2-one (342 mg, 44 95) as a colorless oil. MO-IER tp/2 calc. 273.20926, found 274.2 (M.-1)k; retention time: 2.03 min. (Method of RH B).

Stage 3: 3-(3,3-dimethylbutyl)-4-methyl-pyrrolidin-2-one

To a 50 mL nitrogen-purged flask charged with 1-benzyl-3-(3,33-dimethylbutyl)-4-methylpyrrolidin-2-one (342 mg, 1.251 mmol) was added propan-1-amine (6 mL) and ethane-1,2-diamine (500 μL, 7.479 mmol). The solution was cooled to -30 "С and a strip of lithium wire (6 cm, cut into 6 smaller pieces and washed with hexane to remove excess oil) was added. The flask was again equipped with a septum, and the reaction mixture was vigorously stirred with slight heating to -20 "С. As a result, a blue color formed around the lithium wire, which briefly passed into the solution, and the reaction mixture was allowed to stir until the solution finally turned dark blue (20 min).

Water (15 ml) was added, large pieces of lithium were removed, the mixture was heated to room temperature and stirred for 10 min. The crude mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated by mass to give crude 3-(3,3-dimethylbutyl)-4-methylpyrrolidin-2-one (388 mg, 169 95) in in the form of yellow oil, which was used without additional purification. MO-IER tt/2 calc. 183.16231, found 184.1 (M.-1); retention time: 1.43 min. (Method of RH B).

Stage 4: (145)-8-I3-(3,3-dimethylbutyl)-4-methyl-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18, 23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (hydrochloride salt) (Compound 97) she M M and Verkh M ME m M - her

(145)-8-chloro-12,12-dimethyl-2A6b-thia was added to a vial filled with crude 3-(3,3-dimethylbutyl)-4-methylpyrrolidin-2-one (22 mg, 0.1200 mmol) -3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione ( 25 mg, 0.05373 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthene-4-ylodiphenylphosphane (8 mg, 0.01383 mmol), (1E, 4E)-1,5-diphenylpenta-1,4 -dien-3-one; palladium (13 mg, 0.01420 mmol), C52CO3 (23 mg, 0.07059 mmol), and dioxane (1 mL). The free space above the product was purged with nitrogen, the tube was sealed, and the reaction mixture was stirred at 120 "C for 18 hours. After cooling to room temperature, the crude mixture was diluted with ethyl acetate (-30 mL) and washed with 1.0 M aqueous citric acid (5 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated by mass. The crude residue was dissolved in a minimal amount

From dimethyl sulfoxide (0.4-1 ml) and purified by HPLC (C18 reversed-phase, from 1 95 to 99 95 acetonitrile in water with a modifier of hydrochloric acid).

Then the pure fractions were concentrated n Mascio and the residue was further purified by chromatography on silica gel (from 0 95 to 70 95 ethyl acetate in hexane), obtaining (145)-8-I3-(3,3-dimethylbutyl)-4-methyl-2-oxopyrrolidine- 1-yl|-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (hydrochloride salt) (compound 97) (2 mg, 6 95) in the form of an off-white solid. MO-IER t/72 calc. 596.31445, found 597.2 (M--1) k; retention time: 2.32 min. (Method of RH B).

Example 141: Preparation of (145)-12,12-dimethyl-8--3-(1-methylcyclohexyl)methyl|-2-oxopyrrolidin-1-yl)-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 101) and new va -- - oh oh and hear Y Iii B

Stage 1: 1-benzyl-Z-diethoxyphosphorylpyrrolidin-2-one

In a 250 ml flask, a solution of 1-benzylpyrrolidin-2-one (5,000 g , 28.53 mmol) in dry tetrahydrofuran (5 ml) dropwise over 5 minutes.

The orange solution was stirred for 1 hour and a solution of 1-chloro(ethoxy)phosphorite|oxyethane (5.170 g, 29.96 mmol) in dry tetrahydrofuran (5 mL) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched with cold ice water (50 mL) and acidified to approximately pH 2.0 by adding aqueous 1.0 M hydrochloric acid.

The aqueous layer was separated and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure to give the crude product (8.74 g). Purification by flash column chromatography on silica gel (10 95 to 100 95 ethyl acetate in hexane was attempted initially for 40 min, but no material was obtained, then 0 to 10 95 methanol in CH2Cl2 was used to elute the product) gave the desired 1 -benzyl-3-diethoxyphosphorylpyrrolidin-2-one (3.31 g, 37 90) in the form of an orange viscous oil. 1H NMR (400

MgGu, DMOO-ab) b 7.38 - 7.31 (t, 2H), 7.31 - 7.25 (t, 1H), 7.25 - 7.21 (t, 2H), 4.49 (ai, 9 - 15.1, 1.4

Gu, 1H), 4.30 (a, U - 15.1 Hz, 1H), 4.15 - 3.98 (t, 4H), 3.31 - 3.14 (t, ЗН), 2.34 - 2.19 (t, 1H), 2.19 - 2.04 (t, 1H), 1.22 (m/o 5ei5 OTG, U - 7.2 Hz, 6H). MO-IER t/2 calc. 311.12863, found 312.2 (Ma1) xx; retention time: 0.93 min. (Method of RH B).

Stage 2: 1-benzyl-3-((1-methylcyclohexyl)methylene|pyrrolidin-2-one (9) (9) o M a | Z y | | 7 // -- o -- G r

EYU--r N a

In a 50 mL flask, sodium hydride (42.40 mg, 47.11 μL, 1.060 mmol, 60 95 dispersion in mineral oil) in three portions (to reduce gas evolution) at 5 "C (ice water bath) in a nitrogen atmosphere. After stirring for 10 minutes, a solution of 1-methylcyclohexanecarbaldehyde (182, 5 mg, 1.446 mmol) in dry tetrahydrofuran (2 mL). It was then stirred at this temperature for 3 hours and quenched with a saturated solution of MNACI (15

From ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were successively washed with water (15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude olefinic product. The crude substance was purified by chromatography on a silica gel column, eluting with 5-60 bo ethyl acetate in hexane. isomers E and 7 eluted together.

Removal of volatile components gives 1-benzyl-3-(1-methylcyclohexyl)methylene|pyrrolidin-2-one (265 mg, 97 g) as a yellow viscous oil and a mixture of isomers E and 2. MO-IER t/2 calcd. . 283.1936, found 284.2 (M.-1) k; retention time: 1.98 min. (Method of RH B).

Stage 3: 1-benzyl-3-((1-methylcyclohexyl)methyl|pyrrolidin-2-one) (c) -O o

1-benzyl-3-(1-methylcyclohexyl)methylene|pyrrolidin-2-one (260 mg, 0.9174 mmol) in the form of a mixture of isomers E and 7 and anhydrous methanol (15 ml ). The flask was purged with nitrogen, then palladium (100 mg, 0.09397 mmol, 10 95 on activated carbon) was added under a nitrogen atmosphere and stirred under a hydrogen atmosphere (balloon) at 50 "C for 2 days. The reaction mixture was allowed to cool to ambient temperature, and the flask was purged with hydrogen, then filtered through a pad of celite.

The filtrate was concentrated to give crude 1-benzyl-3-((1-methylcyclohexyl)methyl|pyrrolidin-2-one (138 mg, 53 95) as a brown resin, which was used in the next step without further purification.

MO-IER t/2 calc. 285.20926, found 286.3 (M--1)w; retention time: 1.98 min. (The method of RH

IN).

Stage 4: 3-(1-methylcyclohexyl)methyl|pyrrolidin-2-one (c) (c)

A 50 ml flask was charged with /1-benzyl-3-K(1-methylcyclohexyl)methyl|pyrrolidin-2-one (164 mg, 0.5746 mmol), propan-1-amine (5 ml) and ethane -1,2- diamine (250 μl, 3.740 mmol) in the indicated order at ambient temperature. The solution was cooled to -35 "C (a dry ice-acetone bath, where 1 or 2 trays of dry ice were periodically added to maintain a constant temperature) and immediately added lithium (40 mg, 5.763 mmol, wire, briefly washed with hexane, then freshly cut into small pieces).A blue color began to develop around the small pieces of lithium, and the final dark blue coloration occurred after 1 h. The reaction was quenched with saturated ammonium chloride (5 mL) at -35 °C and the reaction mixture was allowed to warm to ambient temperature . Volatiles were removed under reduced pressure, and the aqueous residue was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and the volatiles were removed under reduced pressure. After drying in vacuum, crude 3-((1-methylcyclohexyl)methyl|pyrrolidin-2-one (78 mg, 70 95) was obtained as a white semi-solid substance and used without further purification. MO-IER tt/2 calc. 195.16231 , found 196.1 (M.-1), retention time: 1.47 min (Method RH B).

Stage 5: (145)-12,12-dimethyl-8-(3-(1-methylcyclohexyl)methyl|-2-oxopyrrolidin-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo |1 7.3.1.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 101) o (6) B (in ) Ku

Mn and ss | y: o uv | and

SI M M -ya M 4 M ya tn Dt

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (25 mg,

Zo 0.05373 mmol), 3-(1-methylcyclohexyl)methyl|pyrrolidin-2-one (10 mg, 0.05120 mmol), Rag(aba)z (8 mg, 0.008736 mmol), xanthophos (5 mg , 0.008641 mmol), cesium carbonate (87.52 mg, 0.2686 mmol) and anhydrous dioxane (0.4 mL). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120"C for 15 hours. The reaction mixture was diluted with dimethyl sulfoxide (1000 μl), microfiltered and subjected to reversed-phase preparative HPLC (C18) using a gradient of acetonitrile in water (from 1 Pho to 99 9o in 15 minutes) and hydrochloric acid as a modifier. The pure fractions were collected and combined, a little brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane, and the organic phase was dried over sodium sulfate, then filtered.

Evaporation of the filtrate gave 10 mg of solid. The product was further purified by flash chromatography on silica gel using a gradient of methanol (from 0 90 to 5 905 in 30 min) in dichloromethane to give (145)-12,12-dimethyl-8-13-(1-methylcyclohexyl)methyl|-2 - oxopyrrolidin-1-yl)-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexane-2,2,4-trione (compound 101) (6.4 mg, 1995) as an off-white solid. IN NMR (400 MHz, DMSO-ab) 5 12.41 (5, 1H), 7.68 (ai, U - 8.5, 1.4 Hz, 1H), 7.61 - 7.47 (t, 2H), 7.04 (a, U - 7.1 Hz, 1H), 6.97 (bhogaa a, U - 9.0 Hz, 1H), 6.70 (a, U - 8.5 Hz, 1H), 4.11 - 3.65 (t, ЗН), 3.10 (Bg 5, 1H), 2.94 (a, U - 13.3 Hz, 1H), 2.75 - 2.57 (t, 2H), 2.43 - 2.28 (t, 1H), 2.10 (g 5, 1H), 2.02 - 1.93 (t, 1H), 1.89 - 1.64 (t, ЗН) , 1.64 - 1.37 (t, 1З3Н), 1.35 - 1.10 (t, 8Н), 0.89 (y,

In - 1.7 Hz, ЗН). MO-IER t/72 calc. 608.31445, found 609.3 (M--1)k; retention time: 2.34 min. (Method of RH B).

Example 142: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9, 11,21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 103 ) and 12,12-dimethyl-8-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11, 21-tetraazatetracycloi|18.2.2.111,14.05,19|Ipentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 104)

Y M Y U - in He

Stage 1: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11, 21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,29(24),21-hexane-2,2,4-trione (enantiomer 1) (Compound 103) and 12,12-dimethyl-8-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11,21 - tetraazatetracycloi|18.2.2.111,14.05,1d0|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (enantiomer 2) (Compound 104) (in in AJ dl

Racemic 12,12-dimethyl-8-(3-12-(1-«-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11, 21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (71 mg, 0.1095 mmol) subjected to chiral separation by means of NCR-chromatography using SpigaISe! О0О-Н (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 42 95 acetonitrile/methanol (90:10)/58 95 carbon dioxide at 10 ml/min for 8.0 min (input volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10) with obtaining as the first eluted enantiomer 12,12-dimethyl-8-(3-12-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1 H -pyrazol-1-yl)-19-oxa-2A6-thia- 3,9,11,21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24 ),21-hexane-2,2,4-trione (enantiomer 1) (Compound 103) (19.77 mg, 56,905) as a white solid; MO-IER t/7 calcd. 648.2342, found 649 ,2 (M--1)x; Retention time: 2.38 min (Phase E method) and as the second eluted enantiomer 12,12-dimethyl-8-(3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy )- 1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9,11,21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9, 20(24),21-hexane-2,2,4-trione (enantiomer 2) (compound 104) (20.25 mg, 57 90) as a white solid 1H NMR (400 MHz, DMSO-ab) 5 12.46 (5, 1H), 8.77 (5, 1H), 8.19 (y, U - 2.68

Hz, 2H), 7.88 (a, U - 8.3 Hz, 1H), 7.03 (a, 9 - 8.7 Hz, 1H), 6.92 (y, U - 8.3 Hz, 1H), 6.11 (a, -2.7 Hz, 1H ), 4.31 (, 9 - 7.0 Hz, 2H), 2.41 (aa, U - 8.3, 5.3 Hz, 1H), 2.07 (9 - 7.0 Gu, ZN), 2.04 - 1.98 (t, 1H), 1.73 (a, U - 6.4 Hz, 2H), 1.67 (da, U - 7.9, 4.9 Gu, 1H), 1.64 - 1.55 (t, 1H), 1.51 (a, 9 - 11.5 Hz,

OH), 1.16 (aa, U - 9.6, 1.7 Hu, 1H), 1.06 - 0.97 (t, 1H), 0.95 (a, U - 4.3 Hz, 2H), 0.88 (5, 2H), 0.86 - 0.77 (t , 1H). MO-IER t/2 calc. 648.2342, found 649.2 (M'-1)k; retention time: 2.38 min. (Method of RH E).

Example 143: Preparation of 8,8-dimethyl-12-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18Abthia-2,9,11,17,23 -pentaazatetracycloi17.3.1.05,9.010,15|gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (compound 108), 8,8-dimethyl -12-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18A6bthia-2,9,11,17,23- pentaazatetracycloyl17,3.1.05, 9.010,15)|gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (enantiomer 1) (compound 116) and 8,β8-dimethyl-12 -(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18Abthia-2,9,11,17,23-pentaazatetracycloi17.3.1.05,9.010,15| gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (enantiomer 2) (Compound 117)

Med meh and that 7 Vivr1 vivr2 Vir Z vivr -e-N But - - -- --k

M nm Vos mn, M (c) r

KI and | and east

Serb

ON 5 She | ru -Sh-x

N Y | Zivr 5 Mem M Gei

Axes M. 2 M-k MN i i-K -i- eE 7

Axes

Y MU po c) m. ro M M - M Zer 8 / M M si e -k M M -- - -A MN -- -A under all s 7

Vosi o oi I M

N

Me r M i nt M ks M M

UL M M o---its "-) yin - od 7 th epapiyoteg 1 epapiyoteg2

Stage 1: 2-(1-hydroxy-5,5-dimethyl-pyrrolidin-2-yl)acetonitrile

M

- Ah osn - n No. 5 N-butyllithium (127 mL 2.5 M, 317.5 mmol) was added dropwise to dry tetrahydrofuran (270 mL) cooled to -78 °C. During the addition, the internal temperature was maintained below -65 °C. Acetonitrile (13.13 g, 16.7 mL, 319.8 mmol) was then added slowly, maintaining the internal temperature below -70 "C. A white precipitate of lithiated acetonitrile was observed after half of the acetonitrile was added. After 30 min at -78 "C, a solution was added 2,2-dimethyl-1-oxido-3,4-dihydropyrrol-1-ium (11.20 g, 99 mmol) in dry tetrahydrofuran (15 ml) at such a rate that the internal temperature did not rise above -70 °C. The yellow suspension was stirred at -78 "С for 1 h, then quenched with a saturated solution of ammonium chloride (150 ml). After heating to room temperature, the two layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 2-(1-hydroxy-5,5-dimethylpyrrolidin-2-yl)lacetonitrile (17 g, 80 Zv). 9o purity for IN NMR, 89 95 uivYd) a5 a Bhomlp oyi mpisn had aigestsu ibzei g Te pehi "her m/yipoci Tihipeg rigiysaynop. TN NMR (300 MHz, SOSIZ) b 1.04 (5, ZN), 1.18 (5, ZN), 1.48-1.67 (t,

ZN), 1.99-2.06 (t, 1H), 2.59 (a, U - 5.2Hz, 2H), 3.17-3.26 (t, 1H), 4.59 (rg. 5., 1H).

Step 2: 2-(5,5-dimethylpyrrolidin-2-yl)lacetonitrile

Ma Ma eh Uh h y; -6О0--О I )

Zinc (4.9 g, 0.6869 mL, 74.935 mmol) was added in several portions to a solution of 2-(1-hydroxy-5,5-dimethylpyrrolidin-2-yl)lacetonitrile (1.8 g, 8.1707 mmol) in acetic acid (21 mL) in an ice-water bath and the mixture was allowed to warm to room temperature, stirred vigorously and heated to 30 °C for b hours. The crude mixture was filtered and concentrated under reduced pressure to give the crude product, which was neutralized 5

Fo with sodium bicarbonate (100 ml) and extracted with dichloromethane (2 x 100 ml). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product 2-(5,5-dimethylpyrrolidine-2-ylluacetonitrile) (0.9 g, 70 95) as a pale yellow semisolid MO-IER Ip/2 calculated 138.1157, found 139.2 (M.-1) k, retention time: 0.312 min (Method RH I).

Stage 3: tert-butyl 5-(cyanomethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Kk eh nm -0656-O-O- Axes

Di-tert-butyldicarbonate (17.4 g, 18.32 mL, 79.73 mmol) was added to a solution of 2-(5,5-dimethylpyrrolidin-2-yl)acetonitrile (12 g, purity 51.905, 44.28 mmol) and triethylamine (8.712 g, 12 mL, 86.10 mmol) in tetrahydrofuran (100 mL). The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was purified by silica gel chromatography using a gradient of 0 95 to 20 95 ethyl acetate in heptane to give tert-butyl-5-(cyanomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (9.5 g, 63 95) as light yellow oil. MO-IER t/: calc. 238.326, found 261.2 (Ma-Ma)k; Holding time: 2.12 min. (Method RH I).

Stage 4: tert-butyl 5-(2-aminoethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

MH,

Kk

Vos MV-- Vosi

Tert-butyl-5-(cyanomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (9.1 g, 38.2 mmol), ammonia (10 ml of a 7 M solution in methanol, 70 mmol ), methanol (70 ml) and Raney nickel (suspension in water, about 4 g, taken with a spatula without accurate weighing). The mixture was vigorously stirred at room temperature to 1 atmosphere of NO (balloon) for three days. Additionally, Raney nickel (a suspension in water, approximately 6 g, taken with a spatula without accurate weighing) and ammonia (10 ml of a 7 M solution in methanol,

From 70 mmol). The reaction mixture was stirred overnight. The mixture was filtered through a pad of celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain a yellow oil, which was tert-butyl-5-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (8.16 g, yield 83 9o). IN NMR (300 MHz, SOSIZ) ppt 1.16-1.34 (t, ZN), 1.34-1.59 (t, 16H), 1.63-2.00 (t,

AN), 2.60-2.75 (t, 2H), 3.73-3.90 (t, 0.ZH), 3.90-4.05 (t, 0.6H). Two rotamers were observed.

MO-0ER t/» calc. 242.358, found 243.2 (M'-1) xx; retention time: 1.74 min. (The method of RH N).

Stage 5: tert-butyl 2,2-dimethyl-5-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate) chn B 2 o 8 xx

M NA

AND ON | hu M 2

Vos M 2 MV--- MN

IS

Vos

To a solution of tert-butyl-5-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (500.0 mg, 2.063 mmol) in M,M-dimethylformamide (5 ml) was added b-fluoropyridine-2-sulfonamide (302.8 mg, 1.719 mmol) and then potassium carbonate (712.9 mg, 5.158 mmol). The flask was closed with partitions and heated at 90 "С in an atmosphere of nitrogen in an oil bath for 14 hours.

The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 100 95 ethyl acetate to obtain tert-butyl-2,2-dimethyl-5-(2-(b- sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (428 mg, 62,965) as a white solid. 1H NMR (400 MHz, Spiogyogit-a) b 7.48 (1, U - 7.9 Hz, 1H) . in - 6.6

Hu, 1), 3.48 (ad, U - 13.0, 6.9 Hu, 1H), 3.20 - 3.06 (t, 1H), 2.03 - 1.86 (t, 1H), 1.77 (1.9 - 5.3 Hu, 1H), 1.59 (dd , U - 14.4, 7.1 Hu, 1H), 1.46 (5, 9H), 1.39 (5, ЗН), 1.28 (5, ЗН). MO-IER t/: calc. 398.19876, found 399.24 (M'-1); Holding time: 0.63 min. (Method of RH A).

Stage 6: tert-butyl 5-(2-((6-Ce-chloro-6-I3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|isosulfamoyl|- 2-pyridylamino|ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

M 9 Names Gen cOose -E M y 60602020 uk M si -s tm M SI (in) mno i i-K -1 Mn pe go

Vos Vos 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (237.6 mg, 0.6323 mmol) and carbonyldiimidazole (102 .5 mg, 0.6323 mmol) were combined in tetrahydrofuran (3.0 ml) and stirred for 90 min at 50 "C. Then tert-butyl-2,2-dimethyl-5-(2-(b- sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (210 mg, 0.5269 mmol) followed by 1,8-diazabicycloid(|5.4.0)undec-7/-ene (120.3 mg, 118.2 μl, 0.7904 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated , then purified by chromatography on silica gel using a gradient from 100 to dichloromethane to 20 95 methanol in dichloromethane to obtain tert-butyl 5-(2-((6-(2-chloro-6-

IZ-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2-

From pyridylamino|ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (321 mg, 81 95) as a white solid. IN NMR (400 MHz, chloroform-4y ) b 8.22 (5, 1H), 8.14 (a, 9 -8.1 Hu, 1H), 7.54 (y, 9 - 14.9 Hz, 2H), 7.39 (y, U 5 19.1 Hz , 1H), 6.54 (5, 1H), 6.06 (5, 1H), 5.89 (y, U - 2.8 Hz, 1H), 4.36 (I, U - 7.2 Hz, 2H), 3.90 (5, 1H), 3.29 (5, 1H), 3.09 (5, 1H), 2.08 (I, U - 7.3 Hz, 2H), 1.86 (5, 4H), 1.69 (5, 1H), 1.52 (5, 1H), 1.37 (8, 9U - 37.2 Hz, 12H), 1.22 (5, ЗН), 1.06 - 0.99 (t, 2H), 0.78 - 0.70 (t, 2H). MO-IER t/2 calc. 755.248, found 756.2 (M--1)k; Retention time: 0.87 min (RC method A).

Stage 7: 8,8-dimethyl-12-(3-12-(11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18A6bthia-2,9,11,17,23- pentaazatetracyclo!|17.3.1.05,9.010,15)gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (Compound 108) 52 gO

Y B OYI

-03 Ma cha M y t re to MH -0-- -1 MH 7 7

Axes

Solution / tert-butyl-5-(2-C(6-Ce-chloro-6-I(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl| sulfamoyl|-2-pyridylamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (320 mg, 0.4231 mmol) in dichloromethane (2.667 mL) and trifluoroacetic acid (482.4 mg, 323.8 μL, 4.231 mmol ) was stirred at room temperature for 4 hours. The solvents were removed and the residue was dissolved in ethyl acetate. It was washed with 2 mL of saturated sodium bicarbonate solution, the organic layer was collected, the solvent was removed, and the residue was dried in vacuo. The above residue was dissolved in dimethyl sulfoxide (5 mL), molecular weight 3 A sieves and the reaction mixture was stirred for 10 minutes. Then cesium fluoride (192.8 mg, 1.269 mmol) and potassium carbonate (175.4 mg, 1.269 mmol) were added, and the reaction mixture was heated at 130 "C for 24 hours. the mixture was filtered through celite, and the celite layer was washed with ethyl acetate.

The filtrate was washed again with saline and the solvent was removed. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient of 100 95 hexanes to 10095 ethyl acetate to give 8,8-dimethyl-12-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H -pyrazol-1-yl)-18A6-thia-2,9,11,17,23- pentaazatetracycloly 1 7.3.1.05,9.010,15)gricose-1(23),10(15),11,13, 19,21-hexane-16,18,18-trione (compound 108) (145 mg, 55 95) as a light yellow solid. IN NMR (400

MHz, Spiogotogit-4) b 13.95 (5, 1H), 8.50 (5, 1H), 8.24 (a, 9 - 2.8 Hz, 1H), 7.63 (5, 1H), 7.52 (ai, 9 - 8.3, 7.3 Hz , 1H), 7.28 (a, 9 - 7.3 Hz, 1H), 6.49 (a, 9 - 8.3 Hz, 1H), 5.96 (a, U - 2.68 Hz, 1H), 4.85 (5, 1H), 4.42 (1 , 9 7.1 Hz, 2H), 4.24 (5, 1H), 3.01 (5, 2H), 2.59 (y, U - 19.1 Hz, 1H), 2.32 (5,1H), 2710 (y,

In 7.1 Hu, 2H), 1.91 (5, 2H), 1.60 (5, ЗН), 1.13 (5, ЗН), 1.06 - 1.00 (t, 2Н), 0.77 - 0.70 (t, 2Н). MO-

IER t/2 calc. 619.2189, found 620.06 (M--1)k; Holding time: 1.87 min. (Method of RH B).

Stage 8: 8,8-dimethyl-12-(3-12-(11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18A6bthia-2,9,11,17,23- pentaazatetracyclo!|17.3.1.05,9.010,15)gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (enantiomer 1) (compound 116) and 8 . 3.1.05,9.010,15)gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (enantiomer 2) (Compound 117) o o o

KU

M 4 Me --- A - --- d- МН o o oh/y B

So S. vav and M

U - SHY go - Mn - Mn epapioteg 1 epatioteg2

Zo Racemic 8,8-dimethyl-12-(3-12-(11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-1856-thia-2,9,11,17 23- pentaazatetracycloi17.3.1.05,9.010,15)gricose-1(23),10(15),11,13,19,21-hexane-16,18,18-trione (compound 108) (145 mg) was subjected to chiral separation by the NKR chromatography method using SpPigaIRak A5-H (column 250 x 21.2 mm, particle size 5 μm) with a mobile phase of 25 95 acetonitrile/methanol (90:10)3/75 95 carbon dioxide at 70 ml/min (vol. injection volume - 500 μl of a solution of 32 mg/ml in acetonitrile/methanol (90:10)) with obtaining 8,8-dimethyl-12-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy) as the first eluted enantiomer )-1H-pyrazol-1-yl)-18A6-thia-2,9,11,17,23- pentaazatetracycloly 1 7.3.1.05,9.010,15)|gricose-1(23),10(15) ,11,13,19,21-hexaene-16,18,18-trione (enantiomer 1) (compound 116) (46.5 mg, 34 95) 1H NMR (400 MHz, Spiogoitogit-4) b 13.88 (5, 1H), 8.50 (5, 1H), 8.24 (y, U - 2.68 Gu, 1H), 7.64 (5, 1H), 7.52 (9, U - 8.4, 7.3 Hz, 1H), 7.28 (5, 1H), 6.50 (a,

U 8.3 Hz, 1H), 5.96 (9, U - 2.8 Gu, 1H), 4.89 (5, 1H), 4.48 - 4.38 (t, 2H), 4.24 (5, 1H), 3.01 (v, 2H), 2.59 (y, U - 23.4 Hu, 1H), 2.32 (5, 1H), 2.11 (1.9. - 7.1 Hz, 2H), 1.92 (rg5, 2H), 1.61 (4, U - 6.7 Hz, 6H), 1.14 (riv, 2H), 1.07 - 1.00 (t, 2H), 0.79 - 0.71 (t, 2H), MO-IER tp/2 calc. 619.2189, found 620.1 (Ma1) F; Retention time: 1.86 min (LC method B) and as the second eluted enantiomer 8,8-dimethyl-12-(3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl) -1856- thia-2,9,11,17,23-pentaazatetracyclo!|1 7.3.1.05,9.010,15)gricose-1(23),10(15),11,13,19,21-hexane- 16 ,18,18-trione (enantiomer 2) (Compound 117) (66.1 mg, 50 95); IN NMR (400 MHz, chloroform-a) b 13.87 (5, 1H), 8.50 (5, 1H), 8.25 (5, 1H), 7.63 (5, 1H), 7.54 (5, 1H), 7.28 (5, 1H), 6.52 (5, 1H), 5.96 (5, 1H), 4.81 (5, 1H), 4.42 (5, 2H), 4.25 (5, 1H), 3.04 (5, 2H), 2.58 (5, 1H ), 2.33 (5, 1H), 2.11 4.9 - 5.0 Hz, 2H), 1.92 (5, 2H), 1.60 (5, 6H), 1.14 (5, 2H), 1.03 (y, 9 - 5.6 Hz, 2H), 0.75 (5, 2H). MO-IER t/7 calc. 619.2189, found 620.1 (M--1)k; Holding time: 1.86 min. (Method of RH B).

Example 144: Preparation of (145)-12,12,20-trimethyl-8-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab6- thia-3,9,11,23-tetraazatetracyclo!|17.3.1.111,14.05,1d|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (Compound 109)

M 9 r pam | and. | y5 ОН vivr?2

VosM on o ZVier1 M ikh s 2 s -Shn--k y 2 JAN; i'm 0-2

What SIMA, zi 7 - g

M os"

Her M yo

Zhe s U uva U n fen ME s M ikh ober r | ME m M i -02 Y a

ES 5

IY

Vos

Stage 1: tert-butyl (45)-2,2-dimethyl-4-I3-((3-methyl-6-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate

M nt | xx

Axis x M i

HE -- si MU o

Ah oh

ZY os.

To tert-butyl (45)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-i-carboxylate (496 mg, 1.927 mmol) under nitrogen atmosphere in M,M-dimethylformamide (6 ml) was added portionwise Man (154.1 mg, 171.2 μl, 3.854 mmol), and the mixture was stirred at room temperature for 15 minutes. Then b-chloro-5-methylpyridine-2-sulfonamide (398.2 mg, 1.927 mmol) was added and the resulting mixture was stirred at room temperature for 80 minutes.

An additional amount of Man (77.07 mg, 85.63 μl, 1.927 mmol) was added to the stirred solution at room temperature and the reaction tube was closed. The resulting mixture was stirred at 100 C for 14 hours. The cooled reaction mixture was poured into 1 n. citric acid and extracted with ethyl acetate (2X). Organic fractions were combined, dried (sodium sulfate),

filtered and concentrated in vacuo to a clear oil, which was purified by silica gel chromatography using a mobile phase gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl (45)-2,2-dimethyl-4-I3-((Z- methyl-6-sulfamoyl-2-pyridyl)oxy|propyl|Ipyrrolidine-1-carboxylate (336 mg, 41 95). 1H NMR (400 MHz, DMSOSO-ab) b 7.74 (aa, 9 - 7.4, 1.0 Hu, 1H ), 7.39 (y, 9 - 7.4 Hz, 1H), 7.29 (5, 2H), 4.36 (5, 2H), 3.58 (9, U - 8.4, 7.9 Hz, 1H), 2.81 (d, U - 10.1 Hz , 1H), 2.20 (I, 9 - 1.8 Hu, 4H), 1.96 (a, U - 26.1 Hu, 1H), 1.75 (a, 9 2 14.2, 6.9 Hz, 2H), 1.46 (d, U - 7.6 7.1 Hz, 2H), 1.37 (1, U - 10.7 Hz, 13H), 1.25 (5, ZN). MSO-IER t/7 calculated 427.21408, found 428.21 (M'-1) k; time retention: 0.72 min (method RH A).

Stage 2: tert-butyl (45)-4-I3-((6-Ce-chloro-6-(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl) |isolphamoyl|-3-methyl-2-pyridyl|oxy|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate 19) oo

M tane nt y y: on | y go M. in 000727 5-4 te Thx |c) /y I M -- И) es with A

M vo Bos 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (175.8 mg, 0.4678 mmol) and carbonyl diimidazole (75.85 mg, 0.4678 mmol) were combined in tetrahydrofuran (4.678 ml) and stirred for 60 min at 50 "C. Then tert-butyl (45)-2,2-dimethyl-4-I3-( 3-methyl-6-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate (200 mg, 0.4678 mmol) and then 1,8-diazabicyclo|5.4.FOundec-7-ene (71.22 mg, 69.96 μl, 0.4678 mmol), and the reaction mixture was heated at 50 C for 15 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with brine. The organic layers were separated, dried over sodium sulfate , filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100

Fo hexanes to 75 95 ethyl acetate in hexane to obtain in the form of an off-white solid, tert-butyl (45)-4-I3-C(6-C2-chloro-6-(3-(2-P1-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|isolphamoyl|-3-methyl-2-pyridyl|oxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (296 mg, 81 95). MO -IER t/2 calcd 784.2633, found 785.1 (Ma1)g Retention time: 0.84 min (RC Method A).

Stage 3: (145)-12,12,20-trimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-2Ab6-thia- 3,9,11,23-tetraazatetracyclo|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 109 )

GT KU o o o 8 M r o 5-4 o

M vos.

Tert-butyl (45)-4-I3-C6-C2e-chloro-6-I3-(2-(1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-3 -methyl-2-pyridyloxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (296 mg, 0.3769 mmol) was dissolved in dichloromethane (5 ml) and hydrochloric acid (3.5 ml of 4 M in dioxane) was added to the mixture , 14.00 mmol) and stirred at room temperature for 30 min. The reaction solution was concentrated to dryness in vacuo. The resulting material was combined with potassium carbonate (313 mg, 2.265 mmol), cesium fluoride (93 mg, 0.6122 mmol), molecular sieves with A and dimethyl sulfoxide (b ml) in a vial, purged with nitrogen, closed with a lid, heated to 140"C and stirred for 16 hours.

It was cooled to room temperature, and the reaction mixture was filtered, and then purified by reverse-phase preparative chromatography using a C18 column (20-99 95 acetonitrile-water and 5 mM hydrochloric acid) to obtain (145)-12.12 as a white solid. 20-trimethyl-8-(3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-

2Ab-thia-3,9,11,23-tetraazatetracyclo!|17.3.1.111,14.05,1O|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4 -trione (compound 109) (78 mg, 32 Fo). IN NMR (400 MHz, DMSOO-ab) b 12.73 (5, 1H), 8.21 (9.9 - 2.8 Hz, 1H), 7.66 (aa, y - 8.3, 7.0 Hz, 2H), 7.58 (j, 7 - 7.4 Gu, 1H), 6.94 (a, 9) - 68.2 Hz, 1H), 6.12 (a,

U -2.7 Hu, 1H), 5.18 (I, U - 12.2 Hz, 1H), 4.32 (I, U - 7.0 Hu, 2H), 3.96 (y, U - 11.1 Hu, 1H), 3.14 (i,

UuU-8.4Hz, 1H), 2.56 (a, U - 10.8 Gu, 1H), 2.18 (5, ZN), 2.11 - 2.01 (t, ZN), 1.85 (ai, 9 - 11.9, 5.3 Gu, 1H), 1.70 (her, U - 12.9 Gu, 2H), 1.55 (y, U - 39.3 Hz, 8H), 1.22 (d, y - 12.6, 12.2 Hz, 1H), 1.03 - 0.92 (t, 2H), 0.92 - 0.84 (t, 2H). MO-IER t/2 calc. 648.2342, found 649.41 (M--1)k; retention time: 2.38 min. (Method of RH B).

Example 145: Preparation of 20,20-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13 ,14-pentaazatetracycloi|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (Compound 110) oo c)

OM5 oo M

VosM M on poh | with still ber k nt y Zier1 Ka v s sh- y -- -k y i-4

VosM o oo in And yours; in Osh

M M - / - - -A

VosM

Stage 1: tert-butyl 2,2-dimethyl-4-I3-(4-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate

B

OM5 wow 8

Axes and Nm | ve i ON and /

Mind 0-- M /

MN what

tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-i-carboxylate (490 mg, 1.461 mmol) and 1H-pyrazole-4-sulfonamide (215 mg, 1.461 mmol), followed by potassium carbonate ( 710 mg, 5.137 mmol) was dissolved in M,M-dimethylformamide (15 ml) and stirred at 50"С in a sealed vessel with a volume of 150 ml for 48 hours. It was cooled to room temperature, then poured into water (100 ml) and extracted ethyl acetate (2 x 100 mL), combined the organic layers, washed with water (2 x 100 mL), dried (sodium sulfate), filtered, and concentrated. , obtaining tert-butyl-2,2-dimethyl-4-I3-(4-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (400 mg, 71

Pho). NMR (400 MHz, DMSO-ab) b 8.20 (5, 1H), 7.71 (5, 1H), 7.23 (5, 2H), 4.14 (1.9 - 6.7 Hz, 2H), 3.54 (aa, U - 18.0, 10.3 Hu, 1H), 2.74 (d, U - 10.2 Hu, 1H), 2.10 (ai, U - 10.1, 6.4 Hu, 1H), 1.87 (9, y - 13.0, 6.1 Hu, 1H), 1.81 - 1.69 (t, 2Н), 1.38 (а, У - 10.5 Hz, ТОН), 1.34 (а, У - 10.7 Hz, ЗН), 1.24 (5, 5Н). MO-IER t/2 calc. 386.19876, found 387.2 (M--1)x; retention time: 1.49 min. (The method of RH

From E).

Stage 2: tert-butyl 4-I3-I4-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|pyrazole-1 -yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate oo o Y M

X/ 5 M x nki? and he | etc

And a fool - 0602 -4 Me TI

M y o com si r - ge

Vos

Bos 2-chloro-6-I3-(2-1-(tetramethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (335 mg, 0.8916 mmol) and carbonyl diimidazole (143 mg, 0 .8819 mmol) were combined in tetrahydrofuran (4.5 mL) and stirred for 60 min at room temperature. Tert-butyl-2,2-dimethyl-4-13-(4-sulfamoylpyrazol-1-yl)propyl was then added |pyrrolidine-1-carboxylate (200 mg, 0.5175 mmol) and then 1,8-diazabicyclo(/5.4.0undec-7-ene (225 μl, 1.505 mmol), and the reaction mixture was heated at 50 "C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100

Fo hexanes to 100 95 ethyl acetate to obtain in the form of an off-white solid, tert-butyl 4-I3-I4-(2-chloro-6-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy|pyrazole- 1-yl|pyridine-3-carbonyl|Isulfamoyl|pyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (201 mg, 52 95).

MO-ER t/ calc. 743.248, found 744.2 (M-a-1)k; Holding time: 1.84 min. (Method of RH E).

Stage 3: 20,20-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13 ,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 110) (6)

M. I. M

5 and F -- -- 7 and

Vos

Tert-butyl 4-N3-(4-C2H-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazol-1-yl) |propyl|-2,2-dimethylpyrrolidine-1-carboxylate (200 mg, 0.2687 mmol) was dissolved in dichloromethane (5.0 mL) and hydrochloric acid (2.5 mL of 4 M in dioxane, 10.00 mmol) and stirred at room temperature for 30 min.

The mixture was concentrated to dryness under reduced pressure, re-dissolved in ethyl acetate, and then aqueous 2 M sodium carbonate (5 ml) was added, obtaining pH - 10. The solution was extracted with ethyl acetate (2 x 10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The obtained material and potassium carbonate (190 mg, 1.375 mmol), cesium fluoride (65 mg, 0.4279 mmol), molecular sieves ZA and dimethyl sulfoxide (b ml) were combined in a vial, purged with nitrogen, closed with a lid, heated to 1557С , and stirred for 20 hours. Cooled to room temperature and

Zo was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 80 95 ethyl acetate in hexane followed by a second column with a gradient of 100 95 dichloromethane to 10 95 methanol in dichloromethane to give in the form of a white solid 20,20-dimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13, 14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (compound 110) (59.6 mg, 36 95). IN NMR (400 MHz, DMSO-46) 6 12.24 (5, 1H), 8.55 (5, 1H), 8.18 (a, U - 2.68 Gu, 1H), 7.88 (5, 1H), 7.74 (a, U - 8.2 Hz, 1H), 6.89 (a, U - 8.2 Hz, 1H), 6.10 (a, U - 2.7 Hz, 1H), 4.31 (Yi, 9) 2 7.0 Gu, ZN), 4.07 (Yi, U - 11.5 Hz, 1H), 2.17 (aa, U - 7.3, 5.2 Gu, 1H), 2.07 (1, 7 - 7.1 Hz, 4H), 1.93, 9 - 9.3 Hz, 1H), 1.87 - 1.69 (t, 2H), 1.60 (y, U - 12.4 Gu, 1H), 1.49 (5, 6H), 1.37 (I, U - 12.1 Hz, 1H), 1.09 - 0.99 (t, 1H), 0.98 - 0.93 (t, 2H), 0.89 (a, 9 - 11.2 Gu, 2H). MO-IER t/2 calc. 607.2189, found 608.2 (M.-1)k; Holding time: 2.07 min. (Method of RH E).

Example 146. Preparation of (185)-20,20,22-trimethyl-4-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia.-1 ,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1) (Compound 111 ), (185)-12,20,20-trimethyl-4-(3-12-|11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3, 9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 112) and (185)-20 . 16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 2) (Compound 113)

HOUSE

OM and: m Kh

Axes m | - and | Her vier1 I for M SI Mn izh

HER HA POM

ZT, i: y o M o m

M ti i M 4 With add E B add M 5 Vierz

YO What else is M m? Huh 7? hu t S

Seam, so i, ki, in 1 o I aigorizoteg 1 agorizoteg 2

Stage 1: tert-butyl-(45)-4-I3-I4-((2-chloro-6-I(3-(2-1P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-3 -carbonyl|sulfamoyl|-3-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl (45)-4-I3-I4-C2-chloro-6-I3-(2 -P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers)

still r

OoM5 | 7 N | Tk

Vos y o uk M si MN sh-- g o oo

M OM zi tu Z -?

M r y | wow | N Y; -4 Me M i -47 M s M to shshch- - -

Vosi Vos tihiige oi hedioizotege

In a flask containing 2-chloro-M-(5-methyl-1H-pyrazol-4-yl)usulfonyl|)-6-(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazole-1 -yl|Ipyridine-Z-carboxamide (900 mg, 1.734 mmol), potassium carbonate (720 mg, 5.210 mmol) and dimethylsulfoxide (14 ml) were added to a solution of tert-butyl (45)-2,2-dimethyl-4-(Z -methylsulfonyloxypropyl)pyrrolidine-I-carboxylate (699 mg, 2.084 mmol) in dimethyl sulfoxide (2 mL), and the reaction mixture was allowed to stir at 9570 overnight. The reaction mixture was cooled to room temperature, filtered, and purified by HPLC (30-99 90 acetonitrile"' water with 0.1 95 modifier hydrochloric acid to obtain tert-butyl (45)-4-I3-I4-(e-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole- 1-yl|Ipyridine-3-carbonyl|sulfamoyl|-3-methylpyrazol-1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl (45)-4-I3-I4-(2- chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-

B-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (524.1 mg, 40 95). MO-IER tp/2 calc. 757.2636, found 758.5 (M--1) same; retention time: 1.93 min. (Way

РХ 5).

Stage 2: 2-chloro-M-(11-I3-((35)-5,5-dimethylpyrrolidin-3-yl|Ipropyl|-3-methylpyrazol-4-yl sulfonyl-6-(3-(2-P1) -(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide and 2-chloro-M-HP1-(3-(35)-5,5-dimethylpyrrolidin-3-yl|propyl|-5- methylpyrazol-4-yl|sulfonyl-6-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide) (mixture of regioisomers)

9) Kf (in) KU zi ut Beh - and | same

Mk 4 si M in M - M

I- -4 M si -- w- -- 7 7

Axes Axes tihiige oi hedioivgotege (c) M (9) K 7 xx r

SHE STILL | Sh o uk Ks si M nya Y M si M

And also - that nm tihiige oi gedioigotege

Tert-butyl (45)-4-I3-I4-Ce-chloro-6-I3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl) was added to the flask |-3-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl (45)-4-I3-I4-C2-chloro-5 6-I3-(2-P1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (524 mg, 0.6911 mmol) dichloromethane (10 mL) and trifluoroacetic acid (2.7 mL, 35.05 mmol) were added.

The reaction was stirred for 1 hour. at room temperature. Then the reaction mixture was evaporated to dryness and quenched with saturated sodium bicarbonate. The reaction mixture was extracted three times with a solution of dichloromethane:methanol (9:11), dried over sodium sulfate and evaporated, obtaining 2-chloro-methylene chloride. M-11-I(3-((35)-5,5-dimethylpyrrolidine-3- yl|propyl/|-3-methylpyrazol-4-yl|sulfonyl-6-I(3-(2-I11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-

Z-carboxamide and 2-chloro-M-(11-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropyl|-5-methylpyrazol-4-yl|sulfonyl-6-I(3-(2 -11-(Trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (mixture of regioisomers) (435 mg, 96,905). MO-IER Ip/2 calcd 657.2112, found 658.3 ( M.-1)k Retention time: 1.61 min (Method RH E).

Stage 3: (185)-20,20,22-trimethyl-4-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1) (Compound 111), (185 )-12,20,20-trimethyl-4-(3-12-|1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13, 14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 112). (185)-20,20,22-trimethyl-4-(3-12-11-trifluoromethyl)cyclopropylethoxy)-1H-pyrazol-1-yl)-10Abthia-1,3,9,13 ,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (atropoisomer 2) (Compound 113) o B o Y y . g zy i m. | - | scha m | - y re, and veins in vahs to m y: t y y yUY tents, tents for water aigorizoteg 1 agorizoteg 2

In a 74 ml beaker, potassium carbonate (458 mg, 3.314 mmol), cesium fluoride (302 mg, 1.988 mmol) and a solution of 2-chloro-M-(1-I3-((35)-5,5-dimethylpyrrolidine) were added -3-yl|propyl|-3-methylpyrazol-4-yl|sulfonyl-6-I(3-(2-I11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-

Z-carboxamide and 2-chloro-M-(11-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropyl|-5-methylpyrazol-4-yl|sulfonyl-6-I(3-(2 -11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (mixture of regioisomers) (435 mg, 0.6610 mmol) in dimethyl sulfoxide (17.50 mL). The reaction was heated at 160 °C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (30-80 9% acetonitrile in water with a hydrochloric acid modifier) to obtain as the first eluted product (185)-20,20,22-trimethyl-4 (3-- 2-1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2, 4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 1) (compound 111) (32.5 mg, 16 95). "IN NMR (400 MHz, DMSO-ab) b 12.39 (5, 1Н), 8.18 (а, У - 2.8 Hz, 1ТН), 7.86 (5, 1Н), 7.77 (а, У - 8.2 Hz, 1Н), 6.90 (y, У - 8.2 Hz, 1Н), 6.10 (th, 9 -2.7

Hz, TN), 4.38 (aai, U - 14.1, 3.1 Hz, 1H), 4.31 (her, U - 7.0 Hz, 2H), 4.01 (Id, U - 14.0, 2.8 Hz, 1H), 2.06 (ad,

U 8.0, 7.6 Hu, 5H), 1.90 - 1.71 (t, ЗН), 1.55 (5, ЗН), 1.47 (в, ЗН), 1.45 - 1.30 (t, 2Н), 1.10 (5, 1Н), 0.99 - 0.93 (t, 2H), 0.93 - 0.85 (t, 2H). The residual solvent blocks three protons. MO-IER t/7 calc. 621.2345, found 622.3 (M-a-1); retention time: 2.96 min. (Method РХ 0). The second eluted product was (185)-12,20,20-trimethyl-4(3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3 ,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 112) (53.9 mg , 26 95). IN NMR (400 MHz, dimethylsulfoxide-ab) b 12.18 (5, 1H), 8.41 (5, 1H), 8.18 (9, Y - 2.8 Hz, 1H), 7.75 (a, Y - 8.2 Hz, 1H), 6.89 (y, U - 68.2 Hu, 1H), 6.10 (a, U - 2.7 Hu, 1H), 4.31 (9 - 7.0 Hu, 2H), 4.22 (y, U - 13.6, 3.68 Hz, 1H), 4.03 - 3.92 (t, 1H), 2.40 (in, ZN), 2.22 (0, 9 - 11.8

Hz, 1H), 2.11 - 1.91 (t, 5H), 1.83 (a, U - 15.7, 7.4 Hz, 1H), 1.75 (yes, U - 11.9, 5.0 Hz, 1H), 1.51 (a, U - 13.0 Hz , 7H), 1.38 (Y, 9 - 12.2 Gu, 1H), 1.03 (5, 1H), 0.99 - 0.84 (t, 4H). MO-IER t/2 calc. 621.2345, found 622.3 (Ma-1)j; Retention time: 3.01 min (method РХ 0). The third eluted product was (185)-20,20,22-trimethyl-4-(3-12-11-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3 ,9,13,14-pentaazatetracycloi|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (atropoisomer 2) (Compound 113) ( 12.4 mg, b 95). 1H NMR (400 MHz, dimethylsulfoxide-ab) b 12.10 (5, 1H), 8.18 (a, U - 2.8 Hz,, 1H), 7.81-7.70 (t, 2H), 6.88 (j, U - 8.3

Hz, 1H), 6.10 (a, U - 2.68 Hz, 1H), 4.40 - 4.26 (t, ЗН), 4.00 (ada, 9 - 13.5, 10.2, 2.7 Hz, 1H), 2.68 (5,

ЗН), 2.43 - 2.32 (t, 1Н), 2.07 (I, 9 - 7.1 Hz, ЗН), 1.96 - 1.57 (t, 5Н), 1.57 -1.41 (t, 8Н), 1.00-0.84 (t, 4Н) . (2 covered with residual solvent). MO-IER t/2 calc. 621.2345, found 622.4 (MA) k; retention time: 3.08 min. (Method РХ 0).

Example 147: Preparation of 20,20-dimethyl-4-(3-2-(11-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13 ,14-pentaazatetracycloi|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (enantiomer 1) (Compound 118) and 20,20- dimethyl-4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111 ,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 119)

OM ISH ts | M

M ro Mi Vier1 M M g - Mi M dru -schoo t evp -oa kp od

Stage 1: 20,20-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13 ,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 118) and 20,20- dimethyl-4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111 ,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 119)

Racemic /20,20-dimethyl-4-(3-12-11-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (57 mg, 0.09287 mmol) was subjected to chiral separation using NKR-

chromatography using SpigaIRak A5-H (250 X 10 mm, particle size 5 μm) with a mobile phase of 26 95 acetonitrile:methanol (90:10; without modifier)/74 95 carbon dioxide at a speed of 10 ml/min for 8.0 min (injection volume - 70 μl of a 24 mg/ml solution in methanol/dimethylsulfoxide (90:10)3) with obtaining 20,20-dimethyl-4-(3-(2-P1-(trifluoromethyl)) as the first eluted enantiomer cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22 ),12-pentaene-8,10,10-trione (enantiomer 1) (compound 118) (20.76 mg, 74 95) as a white solid. 1TH NMR (400 MHz, DMSO-46) b 12.24 (5, 1H), 8.53 (5, 1H), 8.18 (y, 9 - 2.8 Hz, 1H), 7.87 (5, 1H), 7.73 (a, 9 - 8.2 Hz, 1H), 6.88 (a, U - 8.2 Hz, 1H), 6.09 (a, U - 2.7 Hz, 1H), 4.30 (her, U - 7.1 Hz, ЗН), 4.06 (Y, 9 - 11.7 Gu , 1H), 2.25 - 2.10 (t, 1H), 2.05 (a, U - 9.6, 5.0 Hu, 4H), 1.93 (aa, U - 16.2, 7.1 Hu, 1H), 1.82 (ad, U - 12.4 Hu, 1H), 1.76 - 1.68 (t, 1H), 1.54 (5, 1H), 1.51 (a, U - 15.5 Hz, 6H), 1.37 (i, U - 12.0

Gu, 1H), 1.08 - 0.99 (t, 1H), 0.98 - 0.92 (t, 2H), 0.91 - 0.84 (t, 2H). MO-IER t/2 calc. 607.2189, found 608.2 (Ma1)-4; retention time: 2.07 min. (Method of RH EE). The second eluted enantiomer was 20,20-dimethyl-4-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13, 14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 119) (17.84 mg, 63 95) in the form of a white solid.

MO-ER t/2 calc. 607.2189, found 608.3 (M--1) 4; Holding time: 2.07 min. (Method of RH E).

Example 148: Preparation of 21,21-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13 ,14-pentaazatetracyclo|1 7.2.1.111,14.02,7|gricose-2,4,6,11(23),12- pentane-8,10,10-trione (Compound 122) oM5 h/ M Y

Vos z pk X Zier1 (note: takes

And after m - dm M si ory i

All of them eat

Its m 2 oo

In M

5-47 S s A vyvrz mem MM u dru t AT ri

Stage 1: tert-butyl /2,2-dimethyl-4-(4-(4-sulfamoylpyrazol-1-yl)butyl|pyrrolidine-1-carboxylate oo

OM KU U

Vos Z nm y non nm y - same oh / M

MN or

tert-butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-n-carboxylate (600 mg, 1.717 mmol), 1H-pyrazole-4-sulfonamide (256 mg, 1.740 mmol) and potassium carbonate (850 mg , 6.150 mmol) were combined in M,M-dimethylformamide (15 ml) and stirred at 50 "C in a sealed vessel with a volume of 150 ml for 22 hours. The mixture was cooled to room temperature, poured into water (100 ml) and extracted ethyl acetate (2 x 100 ml), the organic layers were combined,

Zo was washed with water (2 x 100 ml), dried (sodium sulfate), filtered and concentrated.

The orange residue was purified by silica gel chromatography using a gradient of 100 95 dichloromethane to 15 95 methanol in dichloromethane to give tert-butyl-2,2-dimethyl-4-(4-(4-sulfamoylpyrazol-1-yl)) as a colorless oil. butyl|pyrrolidine-1-carboxylate (499 mg, 73 95).IN NMR (400 MHz, DMSO-ab) b 8.19 (5, 1H), 7.71 (5, 1H), 7.23 (5,2H), 4134, 9 - 7.0

Hz, 2H), 3.52 (ai, U - 13.9, 8.6 Hz, 1H), 2.06 (y, 9 - 12.0 Gu, 1H), 1.85 (da, U - 16.6, 10.1 Hz, 1H), 1.80 - 1.71 (t , 2H), 1.42 - 1.34 (t, 13H), 1.32 (9, 9U - 7.2 Hz, ZN), 1.29 (y, 9U - 5.6 Gu, 1H), 1.23 (5,

Academy of Sciences). MO-IER t/2 calc. 400.21442, found 401.2 (MAT); retention time: 1.61 min. (The method of RH

IS).

Stage 2: tert-butyl 4-(4-I4-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazole -1-yl|butyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o 19) oo nd X y on | H V loh mm 4 si lot 5-47 o s A

2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (410 mg, 1.091 mmol)) and carbonyldiimidazole ( 177 mg, 1.092 mmol) were combined in tetrahydrofuran (6.0 ml) and stirred for 90 min at 50 "C. Then tert-butyl-2,2-dimethyl-4-(4-(4-sulfamoylpyrazole-1 -yl)butyl|pyrrolidine-1-carboxylate (257 mg, 06416 mmol) followed by 1,8-diazabicyclo/5.4.FO1undec-7-ene (240 μL, 1.605 mmol), and the reaction mixture was heated at 50 °C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100 95 dichloromethane to 10 95 methanol in dichloromethane, obtaining as an off-white solid tert-butyl 4-

I4-I4-(2-chloro-6-I3-(2-P1-("trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|Isulfamoyl|pyrazol-1-yl|brutil|-2 ,2-dimethylpyrrolidine-1-carboxylate (345 mg, 71 95).

MO-ER t/2 calc. 757.2636, found 758.2 (M--1); Holding time: 1.93 min. (Method of RH E).

Stage 3: 0/0 21,21-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6bthia-1,3,9, 13,14-pentaazatetracycloi17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (Compound 122)

Ge) M (in) M

Eh M xx t mm M Go M Mk 2 M M - i chatu "- -- - --i -- і- VosM іke ko

Tert-butyl 4-I4-(4-Ce-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazol-1-yl) |butyl|-2,2-dimethylpyrrolidine-1-carboxylate (315 mg, 0.4154 mmol) was dissolved in dichloromethane (8.5 mL) and hydrochloric acid (3.25 mL of 4 M in dioxane, 13.00 mmol) was added to the mixture. , and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2 M sodium carbonate (5 mL) was added to a pH of 10. The solution was extracted with ethyl acetate (2 x 10 mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting material was combined with potassium carbonate (290 mg, 2.098 mmol), cesium fluoride (95 mg, 0.6254 mmol), molecular sieves 3 A and dimethyl sulfoxide (10.0 ml) in a vial, purged with nitrogen, closed, heated to 155 "C and stirred for 20 hours. Cooled to

From room temperature and filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100 95 dichloromethane to 10 95 methanol in dichloromethane followed by a second column with a gradient of 100 95 hexanes to 80 95 ethyl acetate in hexane. with obtaining in the form of a white solid 21,21-dimethyl-4-(3-12-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9 ,13,14- pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (compound 122) (131 mg, 50 95 ). IN NMR (400 MHz, DMSO-46) b 12.34 (5, 1H), 8.83 (5, 1H), 8.21 (0.9 - 2.7 Hz, 1H), 7.94 (5, 1H), 7.81 (a, U - 8.4 Hz, 1H), 6.91 (y, U - 8.2 Hz, 1H), 6.12 (a, U - 2.6 Hz, 1H), 4.44 da, U - 11.3, 3.3 Hz, 1H), 4.31 (1, 9. - 7.0 Hz, 2H), 4.19 (da, U - 19.3, 5.9 Hz, 1H), 2.97 (I, U - 9.5 Hz, 1H), 2.33 (aa, y) - 12.1, 8.3 Hz, 1H), 2.08 (I . . ). MO-IER n/2 calc. 621.2345, found 622.3 (MA) k; retention time: 2.16 min. (Method of RH E).

Example 149: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19 ,22-pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5(10),6,8,20,23-hexane-2,2,4-trione (Compound 123)

M - kunt ve and sh | vision? sun and: . Vos, 7 vyuri noz o- a uva IN THEM 4 M i xx where m? hu de -rtalorh

AND

Stage 1: tert-butyl-2,2-dimethyl-4-(A-(b-sulfamoyl-3-pyridyl)amino|butyl|pyrrolidine-1-carboxylate

KI r oo ni xx

ON y: y Vos,. ? and MN

M -- 4l-lzhkhkKp Vos,

M 02 M

IS

In a sealed vial with a volume of 5 ml, a solution of tert-butyl-4-(4-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (507 mg, 1.875 mmol), 5-fluoropyridine-2-sulfonamide (300 mg, 1.703 mmol) and diisopropylethylamine (1.5 mL, 8.612 mmol) in p-ViOnH (3 mL) were stirred at 160 "C for 16 hours. The solvent was removed by mass, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel (from 0 95 to 40 95 ethyl acetate in hexane) to obtain tert-butyl-2,2-dimethyl-4-(4-(b-sulfamoyl-3-pyridyl)amino|butyl|pyrrolidine -1-carboxylate (210 mg, 29 95) MO-IER ip/2 calcd 426.23007, found 427.26 (M'-1)k Retention time: 1.73 min (RC Method B).

Stage 2: tert-butyl 4-(4-C6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-Z- pyridylamino-butyl-2,2-dimethyl-pyrrolidine-1-carboxylate

M Mi ZY oi Men ZI oi si

MNoya o--her 0-7

EC ts

M

/

Bos 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (278 mg, 0.7399 mmol) and carbonyldiimidazole (120 mg, 0 .7401 mmol) were combined in tetrahydrofuran (6 ml) and stirred for 90 min at 50 "C. Then a solution of tert-butyl-2,2-dimethyl-4-I4-((b-sulfamoyl-3-pyridyl) was added amino|butyl|pyrrolidine-1-carboxylate (210 mg, 0.4923 mmol) and 1,68-diazabicyclo/5.4.O)undec-7-ene (190 mg, 1.248 mmol) in tetrahydrofuran (3 mL). The reaction was heated at 50 C overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated, then purified by preparative reversed-phase HPLC (C18, 1 95 to 99 95 acetonitrile in water modified with hydrochloric acid to give a tert -butyl 4-I(4-((6-Ce-chloro-6-|3- (2-P-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-3-

pyridylamino|butyl|-2,2-dimethylpyrrolidine-1-carboxylate (264.4 mg, 68 95). MO-IER t/: calc. 783.27924, found 784.39 (M--1) k; retention time: 0.91 min. (Method of RH A).

Stage 3: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,19,22- pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5(10),6,8,20,23-hexane-2,2,4-trione (Compound 123)

OY PO m-n si es mn y she M -kh Mn -3 -- -A poda u

Vos

Tert-butyl 4-(A-C6-C2-chloro-6-I3-(2-11-trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl| 3-pyridylamino|butyl |-2,2-dimethylpyrrolidine-1-carboxylate (260 mg, 0.3315 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid (2.5 mL of 4 M in dioxane, 10.00 mmol) was added to the solution. and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and the resulting intermediate was combined with potassium carbonate (230 mg, 1.664 mmol), cesium fluoride (80 mg, 0.5266 mmol), molecular sieves with A (300 mg) and dimethylsulfoxide (3 ml) in a 5 ml vial, which was purged with nitrogen and stirred overnight at 150 C. The mixture was cooled to room temperature, filtered and purified by preparative reversed-phase HPLC (C18, from 1 95 to 99 95 acetonitrile in water with the modifier hydrochloric acid to obtain /- 12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6 -thia-3,9,11,1 9,22-pentaazatetracyclo|18.2.2.111,14.05,10|pentacose-1(22),5(10),6,8,20,23-hexane-2,2,4-trione (Compound 123) (8, 7 mg, 4,905). MO-IER t/2 calc. 647.2502, found 648.34 (M'-1) zhk; retention time: 2.2 min. (Method of RH B).

Example 150: Preparation of 21,21-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10Abthia-1,3,9,13,14 -pentaazatetracyclo!|17.2.1.111,14.02,7|tricose-2,4,6,11(23),12- pentane-8,10,10-trione (enantiomer 1) (compound 134) and 21,21-dimethyl -4-(3-12-|(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6bthia-1,3,9,13,14-pentaazatetracycloyl17.2.1.111, 14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 135)

DM Im ik ratro da atra uro pli

Stage (1:0/21,21-dimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3, 9,13,14-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-

Zo 8,10,10-trione (enantiomer 1) (Compound 134) and 21,21-dimethyl-4-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl )-10A6-thia-1,3,9,13,14- pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10- trione (enantiomer 2) (Compound 135)

Racemic /-21,21-dimethyl-4-(3-12-(11-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,13, 14-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (100 mg, 0.1592 mmol) was subjected to chiral NKR- chromatography (SpigaiRak AB-N (250 X 10 mm), column 5 μM; mobile phase - 34 95 acetonitrile/methanol (90:10, without modifier), 66 95 carbon dioxide, 10 ml/min; concentration 24 mg/ml in acetonitrile/methanol/dimethylsulfoxide (80:10:10; no modifier; injection volume 70 μL, 100 bar). The first eluted enantiomer was 21,21-dimethyl-4-(3-(2-(1-

(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,13,14- pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6 ,11(23),12-pentane-8,10,10-trione (enantiomer 1) (Compound 134) (241 mg, 49 95) as a white solid. MO-IER t/: calc. 621.2345, found 622.3 (M--1)4; Holding time: 2.16 min. (Method of RH EE). The second eluted enantiomer was 21,21-dimethyl-4-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10.Ab-thia-1,3,9, 13,14-pentaazatetracycloi|17.2.1.111,14.02,7|tricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 135) (25,4 mg, 51 95) in the form of a white solid.

IER t/2 calc. 621.2345, found 622.3 (М--1)хк; Holding time: 2.16 min. (Method of RH E).

Example 151: Preparation of 12,12,18-trimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 . 138) and 12,12,18-trimethyl-8-(3- (2-P-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11, 18,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (enantiomer 2) ( Compound 139) o oo pokh m cho t» i i u/ovya that m | ru N Yv Vier1 mo. | - o y -4 2 m M i -km M M -- n- 4D'(- 0-y M M M Ge; fell uo ru ro 1 5 epapioteg 1 epapioteg?

Stage 1: 12,12,18-trimethyl-8-(3-12-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (Compound 138) and 12,12,18-trimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11, 18,23- pentaazatetracycloyl17.3.1.111,14.05,10)hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 2) ( Compound 139) o o o 9 Y B m | ro o M | 2 o - - pak - tm ti M -0-ke 0-І M M (in) р р water рр ЯК, in RA

Racemic 12,12,18-trimethyl-8-(3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo !17.3.1.111,14.05,10|tetracose-1(23),5(10),6,68,19,21-hexane-2,2,4-trione (29 mg) was subjected to chiral separation using NKR- chromatography using a Rpepotepeh GG ShX-4 column (250 X 10 mm), particle size 5 μm with a mobile phase of 22 95 methanol (0.1 95 trifluoroacetic acid), 78 9o carbon dioxide at 10 ml/min for 6.0 min ( injection volume - 70 μl - 24 mg/ml in a mixture of methanol:dimethylsulfoxide (85:15)) with obtaining as the first eluted enantiomer

Zo 12,12,18-trimethyl-8-(3--2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23 -pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (enantiomer 1) (compound 138) ( 7.1 mg, 49 95); MO-IER t/: calc. 647.2502, found 648.34 (M. 1)хж; Retention time: 2.38 min. yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane- 2,2,4-trione (enantiomer 2) (compound 139) (9.4 mg, 55,905); MSO-IER t/: calc. 647.2502, found 648.42 (M 1) same; Retention time: 2.38 min (method RH B).

Example 152: Preparation of 12,12,18-trimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,20-pentaazatetracyclo!|17.2.2.111,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 140)

M a u i, nt fe ud. this that fe And another ish S GI in em B si

M to o i

VosM at 5 (th B

OR m? hu s S eh i sh | N | r r m k | | - r - Shk Zier4 -2 M si M M Verz Y- M si M M - -

Eighth VosM

OM with m? skh vag - and skin c)

Stage 1: tert-butyl 2,2-dimethyl-4-3-(methyl(5-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate

M sh from x sho that XX bu | Mo

M MN - - o

M SI

To a 20 mL vial filled with tert-butyl-2,2-dimethyl-4-3-(methylamino)propyl|pyrrolidine-1-carboxylate (350 mg, 1.294 mmol) was added b-chloropyridine-3-sulfonamide (261 mg, 1.355 mmol), potassium carbonate (256 mg, 1.852 mmol) and dimethyl sulfoxide (4 mL). The free space above the product was purged with nitrogen, the test tube was closed and the reaction mixture was stirred at 120 C for 18 hours. It was cooled to room temperature, diluted with ethyl acetate (-40 ml) and the crude mixture was washed with water (10 ml), brine (5 ml) and the organic layer was dried over sodium sulfate, filtered and concentrated to a mass. Column chromatography (silica, shallow gradient from 100 95 hexanes to 100 95 ethyl acetate) gave tert-butyl-2,2-dimethyl-4-3-Imethyl and (5-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1 -carboxylate (109 mg, 20 95) as an off-white solid. MO-IER t/2 calc. 426.23007, found 427.2 (M--1) zhk; retention time: 1.49 min. (Method of RH B).

Stage 2: tert-butyl 4-I3-(5-(C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|methyl-amino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

B r; Oy on xx and y? xx what gr what a xx -

M M M. s --- Mem M si M p i -47 M" ts -

VosM VosM

In a 20 ml vial, filled with 2-chloro-6-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (106 mg, 0.2821 mmol ) was added carbonyldiimidazole (47 mg, 0.2899 mmol) and tetrahydrofuran (2 mL). The vessel was closed and the reaction mixture was stirred at room temperature for 2 hours. At this point, tert-butyl-2,2-dimethyl-4-13- (methyl-(5-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (109 mg, 0.2555 mmol) in tetrahydrofuran (2 mL) and then 1,8-diazabicyclo(|5.4.F) undec-7-ene (60 μL, 0.4012 mmol). The reaction mixture was stirred at room temperature for 18 h and quenched with water (- 4 mL). Aqueous citric acid (x 4 mL, 1 M) was added and the crude mixture was extracted with ethyl acetate (3 x 10 mL).The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by mass.

Column chromatography (silica, gradient from 100 95 hexanes to 100 95 ethyl acetate) gave tert-butyl 4-I3-((5-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazole- 1-yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridyl|methylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (87 mg, 43 95) in the form of an off-white solid. /2 calcd 783.27924, found 784.4 (M--1), retention time: 2.42 min (RC Method B).

Stage C: 2-chloro-M-((6-(3-(5,5-dimethylpyrrolidin-3-yl)upropyl-methyl-amino1|-3- pyridyl|sulfonyl|-6-(3-(2-( 11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide

POM POM

Mem yo si M 7 mem y si M 7 "-K i- - -

VosmM nm

In a vial of tert-butyl 4-(3-C(5-Ce-chloro-6-I3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|- 2-Pyridyl|-methylamino|propyl)|-2,2-dimethyl-pyrrolidine-1-carboxylate (87 mg, 0.1109 mmol) was added to dichloromethane (5 mL), followed by hydrochloric acid (1 mL of 4 M, 4.000 mmol ) in dioxane. The vessel was sealed and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give crude /2-chloro-M-I(6-I3-(5,5-dimethylpyrrolidin-3-yl /upropylmethylamino|-3- pyridyl|sulfonyl|-6-(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide) (75 mg, 99 95) in the form of pale -yellow solid, which was used without further purification, MO-IER t/2 calcd 683.2268, found 684.1 (M'-1)xc, retention time: 1.61 min (RC Method B).

Stage 4: 12,12,18-trimethyl-8-(3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2Ab-thia-3,9,11, 18,20-pentaazatetracyclo!|17.2.2.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-

Zo hexane-2,2,4-trione (Compound 140)

HOUSE pe - pod

Potassium carbonate (140 mg, 1.013 mmol) and C5E (131 mg, 0.8624 mmol) were loaded into a vial with a stirrer. A solution of 2-chloro-M-I((6-(3-(5,5-dimethylpyrrolidin-3-yl)upropylmethylamino |-

Z-pyridyl|sulfonyl|-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (70 mg, 0.1023 mmol) in dimethyl sulfoxide (10 mL) , the vessel was hermetically closed and the reaction mixture was stirred at 200 "C for 1.5 h in a microwave reactor. After cooling to room temperature, the solids were filtered with ethyl acetate eluent. The filtrate was diluted with ethyl acetate (x 60 ml), washed with 1.0 M aqueous citric acid ( 10 mL) and brine (5 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated to wt. -8-(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,18,20- pentaazatetracyclo!|17.2.2.111 ,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

(compound 140) (9 mg, 12 95) as an off-white solid. MO-IER tp/7 calc. 647.2502, found 648.2 (MT) k; retention time: 2.21 min. (Method of RH B).

Example 153: Preparation of 4-I|3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14 22-pentaazatetracyclo|16.2 .1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 141)

M 9

NA U x on mm | p. Zier1

M o t M si 7 a

VosM about oo

M o o o

Uh 7 X X/I/ and | oh m mm M si Med Vier2 | N U -0 sho nu - 0th M M M -1 leads

VosM

Stage 1: tert-butyl 4-I3-I3-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazol-1-yl|Ipropyl| -2,2-dimethyl-pyrrolidine-1-carboxylate

M a OM "co r. co

M | M and Me

M Y 4 si 5-41 M si

VosmM

VocmM 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (107.6 mg, 0.2975 mmol) and carbonyldiimidazole (57.89 mg, 0.3570 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at 50"C. Then tert-butyl-2,2-dimethyl-4-|3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidin- 1-carboxylate (115 mg, 0.2975 mmol) and then 1,8-diazabicyclo[5.4.O0)undec-7/-ene (67.94 mg, 66.74 μl, 0.4463 mmol), and the reaction the mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride solution, followed by brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 100 95 ethyl acetate, obtaining tert-butyl-4-13-3-(e-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|isosulfamoyl|pyrazole- 1-yl|propyl/|-2,2-dimethylpyrrolidine-1-carboxy lat (145 mg, 67 95) as a white solid. 1H NMR (400

MHz, Spiogoitogit-a) b 9.75 (5, 1H), 8.30 (y, 9 - 2.9 Hz, 1H), 8.27 - 8.20 (t, 1H), 7.75 (0, U - 8.4 Gu, 1H), 7.48 1, 9 - 3.1 Hu, 1H), 7.05 (a, U - 2.5 Hz, 1H), 5.97 (a, U - 2.9 Hz, 1H), 4.43 (I, U - 6.68 Hz, 2H), 4.20 (I, 9 - 7.0 Hz, 2H), 3.64 (ai, U - 42.1, 9.1 Gu, 1H), 2.91 - 2.75 (t, 1H), 2.07 (5, 1H), 1.97 (ad,

U - 6.8 Gu, 2H), 1.91 (Her, 9 - 7.7 Hz, 1H), 1.84 (yes, U - 12.1, 5.9 Hz, 1H), 1.69 - 1.54 (t, 4H), 1.43 (y,

U - 4.6 Hu, 11), 1.37 - 1.22 (t, 6H), 0.67 (di, U - 8.4, 5.1 Hz, 2H), 0.50 - 0.38 (t, 4H), 0.32 (H, U - 9.0, 6.8 Hz , 1H), 0.20 (44, 9 - 9.5, 4.9, 3.6 Hz, 2H), 0.14 - 0.06 (t, 2H). MO-IER t/2 calc. 729.30756, found 730.37 (M--1)k; Holding time: 0.91 min. (Method of RH A).

Stage 2: 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10Abthia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02, 7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 141)

(c) KU (c) Ks m x hu Z

Your; gu d- - o VosmM

Solution // tert-butyl-4-(3-3-(2H-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|isosulfamoyl|pyrazol-1-yl) |Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (145 mg, 0.1985 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (150 μL, 1.960 mmol) was stirred at room temperature for 4 h. The solvents were removed and the residue was dissolved in ethyl acetate. It was washed with 2 ml of saturated sodium bicarbonate solution, the organic layer was collected and the solvent was removed, followed by drying the residue under vacuum. The above-mentioned residue was dissolved in dimethyl sulfoxide (3 ml), molecular sieves Z A were added, and the reaction mixture was stirred for 10 min. Then it was added cesium fluoride (94 mg, 0.6188 mmol) and potassium carbonate (86 mg, 0.6223 mmol), and the reaction mixture was heated at 150 °C overnight. purified by reversed-phase HPLC-MS using a double gradient from 50 95 to 99 to mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|- 20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7 | docosa- 2,4,6,11(22),12-pentane-8,10 ,10-trione (Compound 141) (26 mg, 22 95) as a white solid. IN NMR (400 MHz, Spiogotogt-a) b 8.62 (5, 1H), 8.17 (y, y - 2.68 Hz, 1H), 7.67 (a,9 - 8.2

Hz, 1H), 7.48 (a, 9U - 2.3 Hz, 1H), 7.07 (a, 9U - 2.3 Hz, 1H), 7.02 (a, U - 8.3 Hz, 1H), 5.87 (a, U - 2.8 Hz, 1H), 4.41 (y, U - 6.8 Hz, 2H), 4.35 (y, U - 13.3, 3.4 Hz, 1H), 4.00 - 3.87 (t, 1H), 2.754119 - 8.2 Hz, 1H), 2.25 - 1.87 ( t, ЗН), 1.80 - 1.71 (t, 1Н), 1.62 (5, 4Н), 1.59 (5, ЗН), 1.55 (5, ЗН), 1.47 (I, У - 12.3

Gu, 1H), 0.80 (aa, 9 - 12.5, 6.7 Hz, 1H), 0.73 - 0.60 (t, 2H), 0.52 - 0.38 (t, 4H), 0.38 - 0.28 (t, 1H), 0.24 - 0.15 ( t, 2H), 0.11 (dada, - 8.6, 7.2, 3.9, 2.6 Hz, 2H). MO-IER t/72 calc. 593.27844, found 594.2 (M--1) Kk; Holding time: 1.82 min. (method RH b).

Example 154: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11,21 -tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 142)

Mn o

Vost tn Zer1 at «er2 at M ro Ver - | in

KI e)

Ly in c in Zerb

Hay KO - k o Zer4 vos M - z uk M si zu m -y- -A

Es

HER 54 Okh s M y: 7 m east

And more n | r sh | N | 5 -01 m si " Vierb -47 M si M zivr7 - 2NSY in NM

Vos o o o

M

4 m 5 u echai shO 5-47 i M m

Stage 1: tert-butyl 2,2-dimethyl-4-(4-oxobutyl)pyrrolidine-1-carboxylate Vos I

M - - Nn

Dess-Martin periodate (9.59 g, 22.61 mmol) was added to a stirred solution of tert-butyl-4-(4-hydroxybutyl)-2,2-dimethylpyrrolidine-I-carboxylate (5.2 g, 19.16 mmol ) in anhydrous CH2CI2 (35 ml) at 0 "C (ice bath) in a nitrogen atmosphere. In 15 minutes, the reaction mixture was allowed to warm to ambient temperature (and stirring was continued for another 3 hours. The reaction mixture was diluted with ether (200 ml) and slowly saturated aqueous sodium bicarbonate (100 mL) was added (to reduce the evolution of carbon dioxide gas). Then 10 95 sodium thiosulfate (50 mL) was added and the mixture was stirred at ambient temperature for 30 minutes. The layers were not clearly separated, so the mixture was filtered through a filter fritted funnel. The layers were separated from the filtrate, and the aqueous layer was extracted with ether (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give m of raw material. The crude product was purified by chromatography on silica gel (gradient 5-40 95 ethyl acetate in hexane) to give the desired tert-butyl-2,2-dimethyl-4-(4-oxobutyl)pyrrolidine-1-carboxylate (4.39 g, 85 95) in the form of a transparent viscous material. 1N

NMR (400 MHz, Meshapo!-a4) 6 4.48 (I, U - 5.5 Hu, 1H), 3.64 (NP, U - 4.8 Hu, 1H), 2.86 (19, U - 10.6, 5.2

Gu, 1H), 2.30 (Y, 9 - 7.3 Gu, 1H), 2.22 - 2.06 (t, 1H), 1.95 (ad, U - 17.2, 11.6, 5.8 Hz, 1H), 1.67 - 1.53 (t, 2H) , 1.53 - 1.48 (t, 2H), 1.47 (5, 4H), 1.43 (5, 5H), 1.40 (5, ЗН), 1.39 - 1.34 (t, 2Н), 1.31 (5, ЗН).

MO-0ER t/» calc. 269.1991, found 270.2 (M'-1); Retention time: 1.7 min (method RH B).

Stage 2: tert-butyl 2,2-dimethyl-4-pent-4-ynyl-pyrrolidine-1-carboxylate

Vos GT Vos photo Wed

N

To a stirred solution of tert-butyl-2,2-dimethyl-4-(4-oxobutyl)pyrrolidine-1-carboxylate (3.0 g, 11.14 mmol) in anhydrous methanol (40 ml) at 0 "C (bath with (ice) potassium carbonate (3.39 g, 24.53 mmol) was added, followed by the dropwise addition of 1-diazo-1-dimethoxyphosphorylpropan-2-one (2.1 mL, 13.99 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 h (the reaction was completed within 4 h). The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (50 mL) and washed with brine (20 mL). The aqueous layer again

It was extracted with (2 x 20 mL) ethyl acetate, and the organic layers were combined, washed with brine (20 mL), dried (over anhydrous sodium sulfate), filtered, and concentrated to a clear oil, which was purified by chromatography on silica gel (gradient 0 -20 95 ethyl acetate in hexane) gives the desired tert-butyl-2,2-dimethyl-4-pent-4-ynylpyrrolidine-1-carboxylate (2.29 g, 77 95) as a clear oil. "IN NMR (400 MHz, Meiyapo!-a4) 6 3.72 - 3.57 (t, 1H), 2.86 (I, U -10.7 Hz, 1H), 2.27 - 2.07 (t, 4H), 1.95 (ada, 9 - 16.7 , 12.2, 6.1 Hu, 1H), 1.58 - 1.48 (t, 4H), 1.47 (5, 5H), 1.43 (5, 5H), 1.41 (5, 2H), 1.31 (5, ZN). /: calcd 265.2042, found 266.2 (M.-1) k, retention time: 1.77 min (Method RH B).

Stage 3: tert-butyl 2,2-dimethyl-4-(5-(5-sulfamoyl-2-pyridyl)pent-4-ynyl|pyrrolidine-1-carboxylate

Vos Her" t | x y tm 4 M | K Vos - xx w 9) --3 a m dk

Tert-butyl-2,2-dimethyl-4-pent-4-ynylpyrrolidine-1-carboxylate (700 mg, 2.638 mmol), b-chloropyridine-3-sulfonamide (900 mg, 4.672 mmol), copper iodide (51 mg, 0.2678 mmol), bis(triphenylphosphine)palladium chloride (112 mg, 0.1596 mmol), and anhydrous M,M-dimethylformamide (b mL) in the indicated order. Nitrogen was then bubbled through the stirred dark mixture for 3 minutes, diisopropylamine (700 μL, 4.995 mmol) was added, and the vessel was sealed under nitrogen. The reaction mixture was stirred at 52 "C for 11 hours, then cooled to ambient temperature, poured into water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed sequentially with water (2 x 50 mL) and brine (30 mL), dried (over anhydrous sodium sulfate), filtered and concentrated under reduced pressure to an orange oil, which was purified by chromatography on silica gel using a gradient of 15-50 905 ethyl acetate in hexane to give the desired tert-butyl-2, 2-Dimethyl-4-15-(5-sulfamoyl-2-pyridyl)pent-4-ynyl|Ipyrrolidine-1-carboxylate (699 mg, 63 95) as a white solid. 1H NMR (400

MGu, Meitshapo!-a4) b 8.91 (aa, U - 2.4, 0.9 Hz, 1H), 8.20 (aa, U - 8.3, 2.4 Gu, 1H), 7.60 (aa, 9 - 8.2, 0.9 Hz, 1H), 3.71 - 3.63 (t, 1H), 2.90 (1, U - 10.7 Hz, 1H), 2.53 (I, U - 6.68 Hz, 2H), 2.28 - 2.14 (t, 1H), 2.03 - 1.92 (t, 1H) , 1.74 - 1.62 (t, 2H), 1.62 - 1.50 (t, ЗН), 1.47 (5, 5Н), 1.43 (5, 5Н), 1.42 (5, 2Н), 1.32 (5, ЗН). MO-IER t/2 calc. 421.20352, found 422.3 (Ma1)f; retention time: 1.74 min. (Method of RH B).

Stage 4: tert-butyl 2,2-dimethyl-4-(5-(5-sulfamoyl-2-pyridyl)pentyl|pyrrolidine-1-carboxylate (9) (6) and 8-o N.M.

M M - and | o -- - --k Vos y a de ve

Nitrogen was bubbled through a stirred solution of tert-butyl-2,2-dimethyl-4-(5-(5-sulfamoyl-2-pyridyl)pent-4-ynyl|pyrrolidine-1-carboxylate (698 mg, 1.656 mmol) in ethanol ( 20 ml). Then platinum oxide (76 mg, 0.3347 mmol) was added under a nitrogen atmosphere and the reaction mixture was stirred in a hydrogen atmosphere (balloon) at ambient temperature. After 2 hours, more platinum oxide (110 mg, 0.4844 mmol) was added ) and the reaction mixture was stirred for another 3 hours. Then the reaction mixture was purged with nitrogen, 5 g of Celite was added and stirred for 20 min. The heterogeneous mixture was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to obtain crude material, which was purified by chromatography on silica gel (gradient 5 -50 95 ethyl acetate in hexane) to obtain tert-butyl-2,2-dimethyl-4-(5-(5-sulfamoyl-2-pyridyl)pentyl|pyrrolidine-1-carboxylate (655 mg, 93 95) in the form of a white 1H NMR (400 MHz, Meshapo!1-a4) b 8.90 (aa, 9 - 2.4, 0.8 Hz, 1H), 8.17 (aa, U - 8.2, 2.4 Gu, 1H), 7.4 7 (aa, U - 8.2, 0.68 Hu, 1H), 3.66 - 3.58 (t, 1H), 2.91 - 2.80 (t, ЗН), 2.19 - 2.05 (t, 1H), 1.98 - 1.86 (t, 1H), 1.75 (p, U - 7.4 Hz, 2H), 1.47 (v, 5H), 1.43 (5, AN), 1.42 (5, 2H), 1.40 (v, 2H), 1.36 (5, 6H), 1.30 (5 , ZN). MO-IER t/: calc. 425.23483, found 426.3 (M--1) t; retention time: 1.73 min.

Zo (Method RH B).

Stage 5: tert-butyl 4-I(5-(5-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|- 2-pyridyl|pentyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

KU Y M--m Zk si and sia 5 /y

ON | r | uva SHY dl

M x vk M si Sho she Ya-0 7 /y

Vos

To a solution of /2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|irazol-1-yl|pyridine-3-carboxylic acid (440 mg, 1.171 mmol) in dry tetrahydrofuran (b ml) was added carbonyldiimidazole (195 mg, 1.203 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was stirred at this temperature for 3 h to form an activated acid. To the activated acid solution was added a solution of tert-butyl-2,2-dimethyl-4-15-( 5-sulfamoyl-2-pyridyl)pentylpyrrolidine-1-carboxylate (500 mg, 1.175 mmol) in dry tetrahydrofuran (4 mL), then 1,8-diazabicyclo|5.4.Fundec-7-ene (400 μL, 2.675 mmol), and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed under reduced pressure and the thick residue was partitioned between water (15 mL) and ethyl acetate (30 mL). The mixture was acidified with aqueous 4 M hydrochloric acid to pH 3-4 and the layers separated The organic phase was washed with saline solution (20 ml) and the combined aqueous layers were re-extracted with ethyl acetate ( 30 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude material. The crude product was chromatographed (silica gel column, elution with a gradient of 0-80 95 ethyl acetate in hexane) to obtain tert-butyl-4-(5-(5-C(e-chloro-6-I3-(2-P1-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-2- pyridyl|pentyl|-2,2-dimethylpyrrolidine-1-carboxylate (750 mg, 82 95) as a white foam. NR NMR (400

MHz, Meiipapo!1-a4) b 9.02 (da, 9 - 2.3, 0.8 Hz, 1H), 8.69 (5, 1H), 8.32 (a, 9 - 1.0 Hz, 1H), 8.32 - 8.29 (t, 1H) . . Hz, 1H), 2.10 (1, 9 - 7.0 Hz, 2H), 1.92 (19, U - 13.9, 13.4, 6.0 Hz, 1H), 1.80 - 1.69 (t, 2H), 1.46 (5, 5H), 1.42 (5, 4H), 1.41 (5, 2H), 1.39 (5, ЗН), 1.36 (в, 6Н), 1.29 (5, ЗН), 1.03 - 0.96 (t, 2Н), 0.82 (Y, У - 5.4 , 2.9 Hz, 2H). MO-IER t/2 calc. 782.284, found 783.4 (Ma1)k; retention time: 2.42 min. (Method of RH B).

Step 6: 2-chloro-M-((6-(5-(5,5-dimethylpyrrolidin-3-yl)pentyl|-3-pyridyl|sulfonyl|-6-(3-(2-(1- (trifluoromethyl )cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) (c) 5-4 o o3/?

M C, - y -5E o- t-m M si M mm Z s M n - -0 - 2Her in NM

Vos

To the solution tert-butyl 4-(5-(5-C2-chloro-6-I(3-(2-(11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| -2-pyridyl|pentyl|-2,2-dimethylpyrrolidine-1-carboxylate (750 mg, 0.9575 mmol) in anhydrous CH2Cl2 (15 mL) was added hydrochloric acid (6.0 mL, 4.0 M in dioxane, 24 .00 mmol) at 0 "C (ice bath) under a nitrogen atmosphere. After 5 minutes, the bath was removed and stirring was continued at room temperature for another 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The residue was placed in ethyl acetate (30 mL) and brought to pH to -- 5 by adding saturated aqueous sodium bicarbonate. The layers were separated and the aqueous portion was re-extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure dry, obtaining 2-chloro-M-I(6-(5-(5,5-dimethylpyrrolidin-3-yl)upentyl|-3-pyridyl|sulfonyl/|-6-(3-(2-(1-" trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine -3-carboxamide (dihydrochloride salt) (720 mg, 99 95) as a white solid.

MO-ER t/2 calc. 682.23157, found 683.4 (M--1)k; retention time: 1.65 min. (Method of RH B).

Stage 7: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,21-tetraazatetracyclo| 18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 142)

Oh oh

N | t m y tm M M M 7 sh -K A

I - 2NSi 7 nm

2-chloro-M-I((6-(5-(5,5-dimethylpyrrolidin-3-yl)pentyl|)-3-pyridyl|sulfonyl|-6-I3-(2-(1) was loaded into a 20 ml bottle -(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (dihydrochloride salt) (715 mg, 0.9456 mmol), potassium carbonate (650 mg, 4.703 mmol), cesium fluoride (215 mg, 1.415 mmol ) and anhydrous dimethyl sulfoxide (15 mL). The vessel was purged with nitrogen for 2 minutes, capped, and stirred at 165 °C for 24 hours. The reaction mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (50 mL) and ice water (50 The layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layers were extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. second column with silica gel (0 95-10 95 methanol in dichloromethane), obtaining 12,12-dimethyl-8-(3-(2-/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl )-2A6b-thia-3,9,11,21-tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2, 4-trione (compound 142) (221 mg, 36 95) as a white solid. 1H NMR (400 MHz, DMSOO-ab) b 12.56 (5, 1H), 9.02 (5, 1H), 8.31 (5, 1H), 8.20 (a, 9 - 2.8

Hu, 1H), 7.93 (a, U - 8.2 Hu, 1H), 7.63 (a, U - 8.2 Hz, 1H), 6.95 (a, U - 8.3 Hu, 1H), 6.12 (a, U - 2.7 Hz, 1H), 4.32 (her, 9 - 7.0 Hz, 2H), 3.08 - 2.93 (t, 1H), 2.91 - 2.78 (t, 1H), 2.49 - 2.41 (t, 1H), 2.084119 - 7.0 Hz, 2H), 2.02 - 1.87 (t, ZN), 1.85 - 1.66 (t, 2H), 1.55 (5, 4H), 1.49 (5, ZN), 1.43 (Her, U - 11.9 Gu, 1H), 1.33 - 1.22 (t, 2H), 0.96 (d, U - 4.68, 4.2 Hz, 2H), 0.92 - 0.87 (t, 2H), 0.85 (5, 1H), 0.62 (5, 1H), - 0.31 (5, 1H). MO-IER t/2 calc. 646.2549, found 647.5 (M.-1)k; retention time: 1.94 min. (Method of RH B).

Example 155: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6b-thia-3,9,11 22- tetraazatetracyclo|18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 143)

МН, чн Мо олбно ер?

I" 4 M

Vos - and K-er same | And water I ХГ о ше до

Ii Ba nat with 7 | ON vierz 5-47 ZM o 4 vivra - M in sh- -- vos M i -5 M si in F - ro Es

M

/

Vos o o, uva i Y 54

N | and n and

OH IFedo o Zer 5 M o sh- -- i -- o / M M M - her tsny

Stage 1: tert-butyl 2,2-dimethyl-4-(5-(6-sulfamoyl-3-pyridyl)pent-4-ynyl|pyrrolidine-1-carboxylate

AND"

Mn. M 5z-e8-o 4 M

Vos - Y Ko - | at

Hg

Tert-butyl-2,2-dimethyl-4-pent-4-ynylpyrrolidine-1-carboxylate (600 mg, 2.261 mmol), 5-bromopyridine-2-sulfonamide (640 mg, 2.700 mmol), copper (I) iodide (44 mg, 0.2310 mmol), bis(triphenylphosphine)palladium (II) dichloride (96 mg, 0.1368 mmol) and anhydrous M,M-dimethylformamide (b ml) in the indicated order. Nitrogen was then bubbled through the stirred dark mixture for 3 min, diisopropylamine (450 μL, 3.211 mmol) was added and the vessel was sealed under nitrogen. The reaction mixture was stirred at 52 "C for 12 h, then cooled to ambient temperature, poured into water (80 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed successively with water (2 x 50 ml) and brine (30 ml), dried (over anhydrous sodium sulfate), filtered and concentrated under reduced pressure to an orange oil, which was purified by chromatography on silica gel using a gradient of 15 95-50 9o ethyl acetate in hexane

Zo to obtain the desired tert-butyl-2,2-dimethyl-4-(5-(b-sulfamoyl-3-pyridyl)pent-4-ynyl|Ipyrrolidine-1-carboxylate (889 mg, 93 95) as a white solid substances. MO-IER t/2 calcd. 421.20352, found 422.3 (M--1)k; Retention time: 0.72 min. (Method RH A).

Stage 2: tert-butyl 2,2-dimethyl-4-(5-(6b-sulfamoyl-3-pyridyl)pentyl|pyrrolidine-1-carboxylate chn, Ba

M io on | Me 4 | M My xx -- Vos sho dk M

Nitrogen gas was bubbled through a stirred solution of tert-butyl-2,2-dimethyl-4-(5-(b-sulfamoyl-3-pyridyl)pent-4-ynyl|pyrrolidine-1-carboxylate (883 mg, 2.095 mmol) in ethanol. (20 mL) Then, platinum oxide (IM) (240 mg, 1.057 mmol) was added under a nitrogen atmosphere and the reaction mixture was stirred under a hydrogen atmosphere (balloon) at ambient temperature.

After stirring for 2.5 hours, the reaction mixture was purged with nitrogen, 5 g of Celite was added and stirred for 20 minutes. The heterogeneous mixture was filtered through a layer of celite.

The dark filtrate was concentrated under reduced pressure, the residue was dissolved in methylene chloride and filtered again through a pad of silica gel to remove residual platinum black material. After concentration under reduced pressure, the crude product was purified by chromatography on silica gel (5-50 95 ethyl acetate in hexane) to obtain the desired tert-butyl-2,2-dimethyl-4-(5-(6-sulfamoyl-3-pyridyl)pentyl|pyrrolidine) -1-carboxylate (882 mg, 99

Fo) in the form of a white solid. MO-IER t/: calc. 425.23483, found 426.3 (M--1)k; retention time: 1.67 min. (Method of RH B).

Stage 3: tert-butyl 4-(5-(6-(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|- Z-pyridyl|pentyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

More

Kya IY and Z

Vos 7-ya Y o ko yo SI - -ya dp 7

I

Vos

To a solution of /2-chloro-6-3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (773 mg, 2.057 mmol) in anhydrous tetrahydrofuran (8 ml) was added carbonyldiimidazole (340 mg, 2.097 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was stirred at 45 "C for 3 hours with the formation of activated acid. To the activated acid solution was added a solution of tert-butyl-2,2-dimethyl-4-(5 -(6-sulfamoyl-33-pyridyl)pentyl|pyrrolidine-1-carboxylate (875 mg, 2.056 mmol) in anhydrous tetrahydrofuran (3 mL), then 1,8-diazabicyclo|5.4.Oundec-7-ene (650 µL, 4.347 mmol), and the mixture was stirred at ambient temperature for 48 h. The volatiles were removed under reduced pressure and the thick residue was partitioned between water (15 mL) and ethyl acetate (30 mL). The mixture was acidified with aqueous 4 M hydrochloric acid to a pH of -3- 4 and layers

Zo was divided. The organic phase was washed with brine (20 mL) and the combined aqueous layers were re-extracted with ethyl acetate (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude material. The crude product was chromatographed (silica gel column, eluting with a gradient of 0-80 95 ethyl acetate in hexane) to obtain tert-butyl 4-(5-I6-(2-chloro-6-

IZ-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl|-3-pyridyl pentyl|-2,2-dimethylpyrrolidine-1-carboxylate (854 mg, 53 95 ) in the form of white foam. Mo-

IER t/2 calc. 782.284, found 783.5 (M--1) k; retention time: 2.2 min. (Method of RH B).

Step 4: 2-chloro-N-(5-(5-(5,5-dimethylpyrrolidin-3-yl)pentyl|-2-pyridyl|sulfonyl)-6-(3-(2-(1-(trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (hydrochloride salt)

o GOATS ueshikn Don uk yo si -I zhk ee si - a pt- what - - - No

M nm /

Vos

To the mixed solution tert-butyl 4-15-16-(2-chloro-6-(3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|- 3-pyridyl|pentyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (850 mg, 1.085 mmol) in anhydrous methylene chloride (10 mL) was added hydrochloric acid in dioxane (6.8 mL, 4.0 M, 27, 20 mmol) at 0 "C (ice bath) under a nitrogen atmosphere. After 10 minutes, the bath was removed and stirring was continued at room temperature for 30 minutes. The volatiles were then removed under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL) and washed saturated aqueous sodium bicarbonate (20 mL).The aqueous layer was re-extracted with ethyl acetate (25 mL).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain crude 2-chloroform.-M-I(5-(5-(5,5-dimethylpyrrolidin-3-yl) pentyl|-2-pyridyl|sulfonyl)-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide (hydrochloride "salt)) (781 mg, 100 95) in the form of a pale yellow foam. MSO-IER t/72 calcd. 682.23157, found 683.4 (Ma1) xx, retention time: 1.71 min. (Method RH B).

Stage 5: 12,12-dimethyl-8-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,22-tetraazatetracyclo| 18.2.2.111,14.05,10|pentacose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 143) (i Ed o o, d r xx A

Fa essay

Ma M i o /M M si M v M

В -А - -- - - NSI nm

2-chloro-M-I((5-(5-(5,5-dimethylpyrrolidin-3-yl)pentyl)-2-pyridyl|sulfonyl|-6-(3-(2-(11 -(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carboxamide (hydrochloride salt) (0.812 g, 1.128 mmol), potassium carbonate (1.11 g, 8.032 mmol), cesium fluoride (0.258 g, 1.698 mmol) and anhydrous dimethylsulfoxide (25 ml). The vessel was purged with a stream of nitrogen for 2 minutes, closed with a lid and stirred at 165 "С for 17 hours. The reaction mixture was allowed to cool to ambient temperature, the mixture was diluted with ethyl acetate (30 ml) and washed with saturated aq. sodium bicarbonate solution, followed by brine. The organic layers were separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Silica gel chromatography (0-55 905 ethyl acetate in hexane gradient) followed by another silica gel column (0 90- 10 9o methanol in dichloromethane) gave 12,12-dimethyl-8-(3-(2-(/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazo l-1-yl)-2A6-thia-3,9,11,22-tetraazatetracycloi|18.2.2.111,14.05,1d0|pentacose-1(23),5,7,9,20(24),21-hexane -2,2,4-trione (compound 143) (80 mg, 11 95) as a white solid. TN NMR (400 MHz, DMSOSO-a6) b 12.59 (5, 1H), 8.69 (5, 1H), 8.19 (a, U - 2.8 Hu, 1H), 8.14 (a, 9 - 7.9 Hz, 1H), 7.98 (a, U - 8.1 Hz, 1H), 7.91 (a, 9 - 8.3 Hu, 1H), 6.91 (a, U - 8.3 Hu, 1H), 6.10 (a, U - 2.7 Hz, 1H), 4.32 (I , U - 7.0 Hz, 2H), 3.01 - 2.87 (t, 1H), 2.74 - 2.62 (t, 1H), 2.47 - 2.36 (t, 1H), 2.08 (I, U - 7.0 Hz, 2H), 2.03 - 1.82 (t, ЗН), 1.80 - 1.64 (t, 2Н), 1.53 (5, ЗН), 1.50 (5, ЗН), 1.40 (I, У - 12.2 Hz, 1Н), 1.33 - 1.27 (t, 1Н) . 0.03 (t, 1Н). MO-IER t/2 calc. 646.2549, found 647.5 (M.-1)j; holding time: 1.96 min. (Method of RH B).

Example 156. Preparation of 13,20,20-trimethyl-4-(3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10HAbthia-1,3,9,14, 22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 144)

оо ож хня р "ru Zier1 - Zer2 - Zerz si pU-vivri

M--kin - -o- -o- -o

M

What - Zer 5 M Ge vera 3 m-n Osim o and OM

M ch ro nt trU- | and Ver em Me Shk Zier 8

Med uk M s Ya-«( in o all VosM

VosM and OM -Zh

M - m

Stage 1: 1-(4-methoxyphenyl)methyl|-5-methyl-3-nitropyrazole

OM ohm trU- pr m--min (in)

M

1-(bromomethyl)-4-methoxybenzene (2.7 g, 13.43 mmol), acetonitrile (20 mL), 5-methyl-3-nitro-1 H - pyrazole (1.55 g, 12.20 mmol) and potassium carbonate (2.53 g, 18.31 mmol). The mixture was stirred at 80°C for 2 hours, then at room temperature for 3 days before concentration under reduced pressure. The residue was suspended in dichloromethane (80 mL). After stirring for 10 minutes, the mixture was filtered and the filtrate was mixed with silica gel before concentration. The residue was purified by chromatography. on silica gel using a gradient of 0 95 to 30 9o ethyl acetate in heptane to give 1-((4-methoxyphenyl)methyl|-5-methyl-3-nitropyrazole (2.4 g, 80 95) as a yellow solid TIA NMR (300 MHz,

SOSIZ) b 2.25 (5, ЗН), 3.79 (5, ЗН), 5.28 (5, 2Н), 6.67 (5, 1Н), 6.87 (а, У - 8.7 Hz, 2Н), 7.14 (а, 9 - 8.7

Hz, 2H). MO-IER t/ 270.1 (M i Ma). to; Retention time: 1.88 min (method RH I).

Stage 2: 1-(4-methoxyphenyl)methyl|-5-methylpyrazol-3-amine o;M nm trU- trU-

Mi Mk c)

A mixture of 1-(4-methoxyphenyl)methyl|-5-methyl-3-nitropyrazole (2.4 g, 9.707 mmol), MNACI (5 g, 3.268 mL, 93.47 mmol), iron (5 g, 89.53 mmol), EN (20 mL) and water (4 mL) were stirred at 80 "C overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, washing with methanol. The filtrate was concentrated, the residue was suspended in water (50 mL) and extracted ethyl acetate (80 ml). The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-((4-methoxyphenyl)methyl|-5-methylpyrazole-3-amine as a red oil (2 g, purity 91 9o according to LCMS data, yield 86 95). 1H NMR (300 MHz, SOSIZ) 6 2.13

(5, ЗН), 3.78 (5, ЗН), 5.01 (5, 2Н), 5.44 (5, 1Н), 6.83 (y, У - 8.7 Hz, 2Н), 7.04 (й, У - 8.7 Hz, 2Н) . MO-

IER t/2 calc. 217.1215, found 218.2 (M--1)x; Holding time: 1.21 min. (Method RH I).

Stage 3: 1-(4-methoxyphenyl)methyl|-5-methylpyrazole-3-sulfonyl chloride oo nm XM - tru

Mk -- x Mk o (c) and X -5-1-K4-methoxyphenyl)methyl|-5-methylpyrazol-3-amine (20 g, 92 mmol) were dissolved in ASON (60 ml) and formic acid (20 ml ). The mixture was cooled in an ice-methanol bath. Hydrochloric acid (15.2 ml of 12 M, 182 mmol) was then added. After the internal temperature reached about -8°C, a solution of sodium nitrite (6.6 g, 96 mmol) in water (10 mL) was added slowly, maintaining the internal temperature from -57°C to -10°C. The mixture was stirred at the same temperature for 5 min, then this mixture was added with a pipette in parts to the Sisi mixture (2.74

g, 28 mmol), 502 (44 g, 343 mmol) and ASON (60 ml) at room temperature (502 solution in

ASON was obtained by passing gas through ASON at 0 "C). The resulting mixture was allowed to warm to room temperature for 1 hour. The mixture was concentrated under reduced pressure.

The residue was mixed with diethyl ether (200 mL) and ice water (50 mL). There was a lot of black oil that did not dissolve in any of the phases. After the mixture was intensively stirred for minutes, the two layers were separated. The organic layer was washed with water (2 x 50 mL), brine (30 mL) and concentrated under reduced pressure and finally co-evaporated with toluene (60 mL) to give 1-((4-methoxyphenyl)methyl|-5-methylpyrazole -3-sulfonyl chloride (9 g, 33 95) as a brown oil which was used directly in the next step 20 MO-IER t/ calcd 300.0335 found 323.0 (M'Ma) k; Retention time: 2 .05 min (Method RH I).

Step 4: 1-(4-Methoxyphenyl)methyl|-5-methylpyrazole-3-sulfonamide

Kya o o

In khm si trUre nom shk -k tru

Mi -.

H o

Kh

A solution of 1-C4-methoxyphenyl)methyl|-5-methylpyrazole-3-sulfonyl chloride (586 mg, 1.9484 mmol) in dichloromethane (4 mL) was added to a solution of ammonia (15 mL of 0.5 M in 1.4 dioxane, 7 ,5000 mmol), cooled with ice water (partially frozen). After 30 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours before concentration under reduced pressure. The residue was purified by silica gel chromatography using 0 95-70 905 ethyl acetate in heptanes to give 1-(4-methoxyphenyl)methyl|-5-methylpyrazole-3-sulfonamide (200 mg, yield 36 905) as a white solid. MO-IER t/2 calc. 281.0834, found 282.1 (Ma1)f; retention time: 1.49 min. (Method РХ 1).

Stage 5: 5-methyl-1H-pyrazole-3-sulfonamide

M

BA trU-B

MM nt trU- -- my (in) u

A solution of 1-(4-methoxyphenyl)methyl|-5-methylpyrazole-3-sulfonamide (16.3 g, 57.9 mmol) in trifluoroacetic acid (80 mL) was stirred at 80 "C (oil bath) overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using 0-100 90 ethyl acetate in heptanes Fractions containing the desired product were combined and concentrated.

The residue was triturated with dichloromethane (30 mL) to give 5-methyl-1H-pyrazole-3-sulfonamide as a light yellow solid (6741 mg, yield 69 95). IN NMR (300 MHz, DMSO-a6) mp 2.25 (5, ЗН), 6.32 (5, 1Н), 7.28 (5, 2Н), 13.11 (ru. 5., 1Н).

Step 6: tert-butyl 2,2-dimethyl-4-(3-(5-methyl-3-sulfamoyl-pyrazol-1-yl)/propyl|pyrrolidine-1-carboxylate

U oo OoM5 Mi n i» Zh 7 trU- VosM msec VosmM

Tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-i-carboxylate (1.35 g, 4.024 mmol) and 5-methyl-1H-pyrazole-3-sulfonamide (638 mg, 3.958 mmol) ), and then potassium carbonate (1.95 g, 14.11 mmol) was dissolved in M,M-dimethylformamide (41.32 ml) and stirred at 80 "С in a sealed vessel with a volume of 150 ml for 20 hours. It was cooled, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL), combined organic layers, washed with water (2 x 100 mL), dried (sodium sulfate), filtered, and concentrated The orange residue was purified by silica gel chromatography using gradient from 100 905 hexanes to 100 95 ethyl acetate to give tert-butyl 2,2-dimethyl-4-13-(5-methyl-3-sulfamoylpyrazole) as a colorless oil which turned into a white solid when dried in vacuo 1- yl)upropyl|pyrrolidine-1-carboxylate (419 mg, 52 95).IN NMR (400 MHz, DMSO-46) b 7.31 (5, 2H), 6.36 (5, 1H), 4.05 (Her, U - 6.4 Hz, 2H), 3.54 (yes, 9 - 18.2, 8.1 Hz, 1H), 2.77 (4.9 - 10. 2 Hz, 1H), 2.31 (a,

U same 15.4 Hu, ZN), 2.12 (y, U - 19.6 Hu, 1H), 1.87 (Id, U - 14.0, 6.4 Hz, 1H), 1.78 - 1.65 (t, 2H), 1.41 - 1.28 (t, 15H ), 1.24 (5, ZN). MO-IER t/2 calc. 400.21442, found 401.2 (Ma1)k; retention time: 1.54 min. (Method of RH E).

Stage 7: tert-butyl 4-I3-I3-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-5 -methyl-pyrazol-1-yl|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

Mk, -4 M si i- sh- until Sun 7 VosM

BosM 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (485 mg, 1.291 mmol) and carbonyldiimidazole (210 mg, 1.295 mmol) were combined in tetrahydrofuran (8.0 mL) and stirred for 90 min at room temperature, then tert-butyl-2,2-dimethyl-4-13-(5-methyl-3-sulfamoylpyrazol-1-yl)propyl was added |pyrrolidine-1-carboxylate (342 mg, 0.8539 mmol) followed by the addition of 1,8-diazabicyclo[5.4.F)undec-7-ene (325 μl, 2.173 mmol), and the reaction mixture was heated at 50 "C for 4 p.m. Reaction time

The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 4-I3-IZ3-Ce as an off-white solid -chloro-6-I3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-5-methylpyrazol-1-yl|Ipropyl|-2,2- dimethylpyrrolidine-1-carboxylate (451 mg, 70 90). MO-IER t/: calcd. 757.2636, found 758.2 (M--1)k; Retention time: 2.32 min (RC Method E) .

Stage 8: 13,20,20-trimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ,14 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 144)

о оо ува Ж Her KU 7ja J y Z -4 y in MM MM M shk 57 pav -- g.

Co,

VosmM i-

tert-butyl 4-I3-I3-C2-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-5-methylpyrazol-1 -yl|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (451 mg, 0.5948 mmol) was dissolved in dichloromethane (11 mL) and 5-hydrochloric acid (4.5 mL of 4 M in dioxane, 18, 00 mmol) and stirred at room temperature for 45 min. The mixture was concentrated to dryness under reduced pressure, re-dissolved in ethyl acetate, and then aqueous 2 M sodium carbonate (5 ml) was added, obtaining pH - 10. The solution was extracted with ethyl acetate (2 x 10 ml), washed with saline, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The obtained material and potassium carbonate (411 mg, 2.974 mmol), cesium fluoride (136 mg, 0.8953 mmol), molecular sieves ZA and dimethyl sulfoxide (13.5 ml) were combined in a vial, purged with nitrogen, closed with a lid, heated to 155"C and stirred for 20 hours.

It was cooled to room temperature and filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 80 95 ethyl acetate in hexane to give 13,20,20-trimethyl-4-( 3-2-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4, 6,11(22),12-pentane-8,10,10-trione (compound 144) (141 mg, 38 95). IN NMR (400 MHz, DMSO-a6) 5 12.68 (5, 1H), 8.19 (a, U - 2.68 Hu, 1H), 7.70 (a, y 8.2 Hu, 1H), 6.88 (9, U - 8.2 Hz, 1H), 6.69 (5, 1H), 6.09 (y, U - 2.7 Gu, 1H), 4.30 (I, U - 7.0 Hz, 2H), 4.10 - 3.94 (t, 2H), 2.82 - 2.71 (t, 1H ), 2.34 (y, U - 68.9 Hz, ZN), 2.13 (aa, U - 6.7, 4.0 Hz, 1Н), 2.09 - 2.02 (t, ZN), 1.96 - 1.80 (t, ZN), 1.77 (aa, U - 11.9, 5.2 Hz, 1H), 1.54 (5, ЗН), 1.48 (5, ЗН), 1.35 (у, - 12.3 Гу, 1Н), 0.99 - 0.92 (t, 2Н), 0.89 (а, 9У - 11.6 Hu, 2H), 0.59 - 0.39 (t, 1H). MO-IER t/27 calc. 621.2345, found 622.2 (M--1) xx; retention time: 2.14 min. (Method of RH E).

Example 157: Preparation of 12,12-dimethyl-8-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2Ab-thia-3,9 ,11,24-tetraazatetracyclo|18.3.1.05,10.011,15)tetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (Compound 147)

M on M nt | In Y

Osm Y nm | and zer M , uva; zivr2 u o o i e 3

E KT va

VosM

Y M vs d- (c) er M - Mich

KT - Fr

VosM

Zo Stage 1: tert-butyl 2,2-dimethyl-5-I3-(b-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine-1-carboxylate ooo ooo M/Y

M nt | xx on y nm M:

VosM? | M ikh i M r, -- (c)

IS

VosmM

To a 20 mL vial was added tert-butyl-5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (631 mg, 2.452 mmol) and anhydrous M,M-dimethylformamide (8 mL). 6095 Man (196 mg, 4.900 mmol) was added portionwise to the solution (CAUTION: evolution of gas) and the mixture was stirred at room temperature for 15 minutes. Then b-fluoropyridine-2-sulfonamide (432 mg, 2.452 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. An additional amount of Mann (98 mg, 2.450 mmol) was added to the stirred solution at room temperature and the reaction vessel was closed. The resulting mixture was stirred at 100 "С for 14 h. The reaction solution was diluted with ethyl acetate, then poured into aqueous 1N citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a clear oil, which was purified by silica gel chromatography using a mobile phase gradient from 100 95 hexanes to 100 90 ethyl acetate to give tert-butyl-2,2-dimethyl-5-I3-((b-sulfamoyl-2-pyridyl)oxy|propyl|pyrrolidine- 1-Carboxylate (350 mg, 35 95) MO-IER t/2 calcd 413.19846, found 414.31 (M--1)xh Retention time: 0.69 min (RC Method A).

Stage 2: tert-butyl 5-I3-C(6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2 -pyridyl|oxy|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o, not» scha Ho) c) B i M - MV-62623 M - d- o-Y TM m si o- TM m si

VosM

BosM 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (387 mg, 1.030 mmol) and carbonyldiimidazole (193 mg, 1.190 mmol) were combined in anhydrous tetrahydrofuran (8 ml) and stirred for 75 min at 50 "C. Then a tetrahydrofuran solution (7 ml) of tert-butyl-2,2-dimethyl-5-I3-((b-sulfamoyl-2- pyridyl)oxy|propyl|pyrrolidine-1-carboxylate (328 mg, 0.7932 mmol) and 1,8-diazabicyclo/5.4.F)undec-7-ene (300 μl, 2.006 mmol). The reaction was heated at 50 "С for 4 h. The reaction was diluted with ethyl acetate and washed with 1 M citric acid, then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100 95 hexanes to 75 95 of ethyl acetate in hexane, obtaining tert-butyl 5-IZ-((6-C(2e-chloro-6-I3-(2-(1-

Zo (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridyloxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (409 mg, 67,965). MO-IER t/: calc. 770.2476, found 771.37 (М-а-1)хж; Holding time: 0.92 min. (Method of RH A).

Stage 3: 12,12-dimethyl-8-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa-2A6-thia-3,9,11 ,24-tetraazatetracyclo|18.3.1.05,10.011,15|hetracose-1(24),5(10),6,8,20,22-hexane-2,2,4-trione (Compound 147)

Iii M r es -sh- (in) M - M ikh kl (in) dO M M

eighth

Tert-butyl-5-I3-C(6-Ce-chloro-6-(3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|g-pyridyl |oxy|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (408 mg, 0.5290 mmol) was dissolved in dichloromethane (7 mL) and hydrochloric acid (4 mL of a 4 M solution in dioxane, 16.00 mmol) was added to the mixture ) and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and the resulting material was combined with potassium carbonate (440 mg, 3.184 mmol), cesium fluoride (130 mg, 0.8558 mmol), ZA molecular sieves, and dimethyl sulfoxide (8 ml) in a vial purged with nitrogen, closed, heated to 140"C and stirred for 16 hours. Cooled to room temperature, filtered and then purified by reversed-phase preparative chromatography using a C18 column (30-99 96 acetonitrile in water - 5 mM hydrochloric acid) to obtain 12,12-dimethyl-8-(3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-19-oxa as a white solid -2A6-thia-3,9,11,24-tetraazatetracyclo|18.3.1.05,10.011,15|hetracose-1(24),5(10),6,8,20,22-hexane-2,2,4 -trione (Compound 147) (17 mg, 5905). MO-IER t/2 calc. 634.2185, found 635.29 (We); retention time: 2.0 min. (Method of RH B).

Example 158: Preparation of 13,20,20-trimethyl-4 (3-2-P1-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 150) and 13,20,20 -trimethyl-4-(3-(2-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4, 6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 151)

Stage 1: 13,20,20-trimethyl-4 (3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9, 14 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 150) and 13,20 20 -trimethyl-4-(3-12-|(1- (trifluoromethyl)cyclopropyl|ethoxy)-1 H-pyrazol-1-yl)-10A6-thia-1,3,9,14 22- pentaazatetracyclo|16.2.1.111 ,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 151) o zu 54 o 5 o x 74

From epipioteg 1 epipioteg 2

Racemic 13,20,20-trimethyl-4-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 22 -pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (114 mg, 0.1815 mmol) was subjected to chiral NKR chromatography. The following NKR protocol was used: SpigaiRak AB-N (150 X 21.2 mm), 5 μm; Mobile phase 35 C: 25 95 acetonitrile:methanol (90:10; without modifier), 75 95 carbon dioxide at 70 ml/min for 8.0 min (injection volume - 70 μl - 32 mg/ml in a mixture of acetonitrile: methanol (90:10) to obtain 13,20,20-trimethyl-4 (3-2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia as the first eluted enantiomer -1,3,9,14 22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 150) (51.27 mg, 91 95) as a white solid. IN NMR (400 MHz, DMSO-ab) b 12.66 (5, 1H), 8.19 (y, 9 - 2.8 Hz, 1H), 7.70 (a, U - 8.2 Hz, 1H), 6.88 (a, U - 8.2 Hz , 1H), 6.69 (5, 1H), 6.09 (a, 9U - 2.7 Gu, 1H), 4.31 (1.7 - 7.0 Hz, 2H), 4.10 - 3.93 (t, 2H), 2.85 - 2.70 (t, 1H), 2.35 (5, ZH), 2.12 (a,9 - 5.6 Gu, 1H), 2.07 (her, 9 - 7.1 Hz, ZH), 1.97 - 1.81 (t, ZH), 1.77 (ad, U - 11.8 . , 2H), 0.52

(a9, y - 15.5, 8.4 Hz, 1H). MO-IER t/ calc. 621.2345, found 622.5 (M--1)k; retention time: 2.19 min. (Method of RH E). The second eluted enantiomer was 13,20,20-trimethyl-4 (3-(2-(11- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9, 14 22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 151) (31.08 mg , 55 95) as a white solid. MO-IER t/: calc. 621.2345, found 622.5 (M--1)k; Retention time: 2.19 min. (Method RH E).

Example 159: Preparation of 21,21-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-10X6-thia-1,3 ,9,14,15-pentaazatetracyclo|17.2.1.02,7.011,15|docosa- 2(7),3,5,11,13-pentane-8,10,10-trione (Compound 152)

KU on t / ush (in)

Zer1 o i uva Vier2

VosM 5-07 M SI

CT -

VosmM o o.o

M

5 riot about

OO m 5-07 M o 7 | with Y "Uh sho- Zer Z -sh

KT o U still m 2 M

CT scan

VosmM

Stage 1: tert-butyl 2,2-dimethyl-4-(2-(3-sulfamoylpyrazol-1-yl)ethoxy|pyrrolidine-1-carboxylate oo

M

5 he th t

T and (c) - from (c)

VosmM

VosM

Dichloromethane (70 mL) was added to a round-bottom flask containing tert-butyl-4-(2-hydroxyethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.94 g, 7.480 mmol) under nitrogen sparging.

The solution was cooled to 0°C before the addition of EtZM (b mL, 43.05 mmol) and methanesulfonyl chloride (1.7 mL, 21.96 mmol). The reaction mixture was stirred for 20 h, allowing it to warm to room temperature in 1 h (clear the solution became cloudy orange in 10 minutes. The reaction mixture was quenched by the addition of water. Dichloromethane was added, then the brine and the organic layer were separated. The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried in vacuo for 1 h to give a yellow oil, which was combined with 1H-pyrazole-3-sulfanulamide (1.1 g, 7.475 mmol) in a round-bottom flask followed by the addition of potassium carbonate ( 2.23 g, 16.14 mmol) and the mixture was dissolved in M,M-dimethylformamide (13 ml). The reaction mixture was stirred at 50 "С in a sealed vessel with a volume of 150 ml for 48 hours. The mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate

(2 x 100 ml), combined organic layers, washed with water (2 x 100 ml), dried (sodium sulfate), filtered and concentrated. The orange residue was purified by chromatography on silica gel using a gradient from 100 95 hexanes to 100 95 ethyl acetate to obtain as the first eluted less polar regioisomer tert-butyl-2,2-dimethyl-4-(2-(5-sulfamoylpyrazole-1-yl uethoxy) pyrrolidine-1-carboxylate (550 mg, 3895). MO-IER t/2 calcd. 388.17804, found 389.1 (M--1)xc; Retention time: 0.56 min (RC Method A).

Stage 2: tert-butyl 4-(2-I3-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazole -1-yl|ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate

M HER M nm y: o y: Me - y on y so Lo;

GT i and | . St. Sh U M si T o - M si Y kt o

CT - 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (183.5 mg, 0.4884 mmol) and carbonyldiimidazole (91.40 mg, 0.5637 mmol) were combined in anhydrous tetrahydrofuran (4 ml) and stirred for 90 min at 50 "C. Then a tetrahydrofuran solution (7 ml) of tert-butyl-2,2-dimethyl-4 -(2-(3-sulfamoylpyrazol-1-yl)ethoxy|pyrrolidine-1-carboxylate (146 mg, 0.3758 mmol) and 1,8-diazabicyclo|5.4.F)undec-7-ene (142.1 μl , 0.9502 mmol). The reaction was heated at 50 "C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 75595 ethyl acetate in hexane to give tert-butyl 4-(2-IZ-C2-chloro-6-I3 -(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|pyrazol-1- yl|Iieethoxy|-2,2-dimethylpyrrolidine-1-carboxylate (162 mg, 58 95) in the form of an off-white solid. MO-IER t/2 calcd. 745.22723, found 746.22 (Ma-1) w; retention time: 0.87 min. (Method RH A).

Stage 3: 21,21-dimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-10Xbthia-1,3,9,14, 15-pentaazatetracyclo|17.2.1.02,7.011,15)docose-2(7),3,5,11,13-pentane-8,10,10-trione (Compound 152)

Oo oo

M

Uh M "sht0-e- o u MU chet tm y M "U ek Y ZAHH o - o- TM m M I

I'm sorry

VosmM

Tert-butyl 4-(2-3-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazol-1-yl| ethoxy|-2,2-dimethylpyrrolidine-1-carboxylate (162

Zo mg, 0.2171 mmol) was dissolved in dichloromethane (3 ml) and hydrochloric acid (1.6 ml of 4 M in dioxane, 6.400 mmol) was added to the mixture and stirred at room temperature for 30 min.

The mixture was concentrated to dryness under reduced pressure and combined with potassium carbonate (180 mg, 1.302 mmol), cesium fluoride (55 mg, 0.3621 mmol), 3 A molecular sieves, and dimethyl sulfoxide (3.5 mL) in a vial, purged with nitrogen , closed, heated to 140 C and stirred for 10 hours. It was cooled to room temperature, filtered and then purified by reverse-phase preparative chromatography using a C18 column (30-99 95 acetonitrile/water and 5 mM hydrochloric acid) to obtain 21,21-dimethyl-4-(3-12) as a white solid -11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-18-oxa-10X6-thia-1,3,9,14,15-pentaazatetracyclo!|17.2.1.02,7.011,15|docose -2(7),3,5,11,13-pentane-8,10,10-trione (compound 152) (45 mg, 34 do). IN NMR (400 MHz, DMSO-46) b 13.14 (5, 1Н), 8.28 (9, 9 - 2.8

Hu, 1H), 7.96 (a, U - 8.3 Hz, 1H), 7.71 (a, 9 - 2.0 Hu, 1), 7.25 (a, U - 8.2 Hz, 1H), 7.05 (y, U - 2.0 Hz, 1H), 6.14 (a, U - 2.68 Gu, 1H), 4.79 - 4.63 (t, 1H), 4.61 - 4.46 (t, 1H), 4.32 (I, 9 - 7.0 Hz, 2H), 4.17 - 3.98 (t , 2H), 3.89 (daa, U - 11.1, 6.4, 2.7 Hz, 1H), 3.39 (da, 9 - 11.0, 4.4 Gu, 1H), 3.00 (y, U - 10.9

Hz, 1H), 2.06 (ai, U - 13.1, 6.6 Hz, ЗН), 1.91 (ad, у - 13.4, 2.7 Hz, 1Н), 1.48 (5, ЗН), 1.38 (5, ЗН), 1.02 - 0.82 (t, 2H), 0.92 - 0.82 (t, 2H). MO-IER t/2 calc. 609.1981, found 610.25 (M--1)k; retention time: 2.04 min. (Method of RH B).

Example 160: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 158 ) o on oo Y Kt eri se, (o) 0) oo (c) chn Y M sh vi xx go yours: V!

EC Mn

MN from Kk

Stage 1: 3-(2-1-"trifluoromethyl)cyclopropyl|ethoxy|pyrrolidin-2-one o on x

Ve MN (c) m" o - - no se g

Potassium hexamethyldisilazide (16 ,0 ml of 0.5 M in toluene, 8,000 mmol) at 0 "C (ice bath) for 2 minutes under a nitrogen atmosphere. The reaction mixture was allowed to gradually warm to ambient temperature overnight (14 h). The reaction mixture was acidified with glacial acetic acid acid (300 μL, 5.275 mmol) and the volatiles were removed at 20 °C under reduced pressure. The aqueous residue was dissolved in ethyl acetate (50 mL) and washed with brine (20 mL). The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to give a brown crude material.The crude product was purified by chromatography on silica gel (0 90-10 96 methanol in a methylene chloride gradient) to give 3-(2-(1-trifluoromethyl)cyclopropyl|ethoxy|pyrrolidin-2-one (285 mg, 33 95) as a white solid substances 1H NMR (400 MHz, Vepgepe-ab) b 6.76 (5, 1H), 4.21 (y, 9 - 9.4, 6.7 Hz, 1H), 3.73 - 3.64 (t, 1H), 3.55 (y, U - 7.3 Gu, 1H), 2.67 (daaa, 9 - 9.3, 7.6, 4.6, 1.2 Gu, 1H), 2.46 (a, 7 - 9.6, 7.1 Hz, 1H), 1.95 (4, U - 14.3, 7.1 Hz, 1H), 1.90 - 1.81 (t, 1H), 1.74 - 1.58 (t, 2H), 0.86 - 0.77 (t, 2H), 0.54 - 0.43 (t, 2H). MO-IER t/2 calc. 237.09766, found 238.1 (MA) k; retention time: 0.9 min. (Method of RH B).

Stage 2: (145)-12,12-dimethyl-8-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!|1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

Zo (Compound 158) o o o o her Kd

M s m? with

Co.) Mn

Mn with Kk

(145)-8-chloro-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1( 23),5,7,9,19,21-hexane-2,2,4-trione (100 mg, 0.2222 mmol), 3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrrolidine-2- he (63 mg, 0.2656 mmol), cesium carbonate (275 mg, 0.8440 mmol), 4,5-bisidiphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.03457 mmol) (xanthophos) and dry dioxane (2 ml) in this sequence. Nitrogen was bubbled through the heterogeneous mixture for 3 min. Rag(aura)Z (20 mg, 0.02184 mmol) was then added under nitrogen and nitrogen was bubbled for another 2 minutes and sealed under nitrogen. The mixture was stirred at 115 °C for 15 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (150 μL, 2.638 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (3.0 mL) and filtered through 0.45 µm PTFE syringe disc filter UUpytap. The sample was purified by preparative reversed-phase HPLC-MS (30-99 95 acetonitrile in water for 15 min (hydrochloric acid as modifier)). Fractions of the desired product were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25 mL) and washed successively with saturated aqueous sodium bicarbonate (2 x 10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure with obtaining (145)-12,12-dimethyl-8-(2-oxo-3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9,11,18 ,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22 ),5,7,9,19(23),20-hexane-2,2,4-trione (compound 158) (31 mg, 1995) as an off-white solid. TIA NMR (400 MHz,

Meipapo!-a4) b 7.78 (ad, 9 - 8.4, 2.0 Hz, 1H), 7.59 (ad, U - 8.4, 4.4 Hz, 1H), 7.53 (ai, U - 8.5, 71 Gu, 1H), 7.16 ( y, U - 7.3 Hu, 1H), 6.65 (a, U - 8.5 Hu, 1H), 4.26 (a, U - 12.5, 8.0 Hu, 1H), 4.22 - 4.00 (t, 2H), 3.97 (a, U - 9.1, 6.8 Hu, 1H), 3.92 - 3.71 (t, 2H), 3.29 - 3.21 (t, 1H), 3.03 (a, U - 13.9 Hu, 1H), 2.86 (I, U - 10.2 Hu, 1H) . - 1.63 (t, 2H), 1.62 (5, ЗН), 1.60 (a, U - 12.0 Hz, 1H), 1.54 (5,

ZN), 1.47 - 1.36 (t, 1H), 0.96 - 0.91 (t, 2H), 0.84 - 0.77 (t, 2H). MO-IER t/2 calc. 650.2498, found 651.4 (M--1) k; retention time: 2.04 min. (Method of RH B).

Example 161. Preparation of 20,20-dimethyl-4-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10Xbthia-1,3,9 ,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa- 2(7),3,5,11(22),12-pentane-8,10,10-trione (compound 164), 20,20 -dimethyl-4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10Abthia-1,3,9,14,22- pentaazatetracyclo| 16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 302) and 20,20-dimethyl- 4-(3-(2-1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10Xbthia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111, 14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 167) on M o o o

Well, about M

M sh7 i What, in M so i; Wierz

B, about Y Zhe Mi si -- se " with ltt koi in ek BK va SCHO; o 5th o m (HER M

Zo Stage 1: tert-butyl 2,2-dimethyl-4-(2-(3-sulfamoylpyrazol-1-yl ethoxy|pyrrolidine-1-carboxylate) o o

ON I

Y U o M-m

VosM

VosmM

Dichloromethane (70 mL) was added to a round-bottom flask containing tert-butyl-4-(2-hydroxyethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.94 g, 7.480 mmol) under nitrogen sparging.

The solution was cooled to 0°C before the addition of EtZM (b mL, 43.05 mmol) and methanesulfonyl chloride (1.7 mL, 21.96 mmol). The reaction mixture was stirred for 20 h, allowing it to warm to room temperature in 1 h (clear the solution became cloudy orange in 10 minutes. The reaction mixture was quenched by the addition of water. Dichloromethane was added, then the brine and the organic layer were separated. The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried in vacuo for 1 h to give a yellow oil, which was combined with 1H-pyrazole-3-sulfanulamide (1.1 g, 7.475 mmol) in a round-bottom flask followed by the addition of potassium carbonate ( 2.23 g, 16.14 mmol) and the mixture was dissolved in M,M-dimethylformamide (13 ml). The reaction mixture was stirred at 50 "С in a sealed vessel with a volume of 150 ml for 48 hours. The mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml), combined organic layers, washed with water (2 x 100 ml), dried (sodium sulfate), filtered and concentrated. The orange residue was purified by silica gel chromatography using a gradient from 100 95 hexanes to 100 95 ethyl acetate to give the second eluted more polar regioisomer, tert-butyl-2,2-dimethyl-4-(2-(3-sulfamoylpyrazol-1-yl) )ethoxy|pyrrolidine-1-carboxylate (475 mg, 33 95). MO-IER t/2 calcd. 388.17804, found 389.1 (M--1)xc; Retention time: 0.52 min. (Method RH A).

Stage 2: tert-butyl 4-(2-I3-C(2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazole -1-yl|ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate

M o o 9/6 nm vkh rya M -M (in) M - --e o- TM M si e-k y w KT va WHAT,

BosM with 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid) (691.7 mg, 1.841 mmol) and carbonyldiimidazole (310.0 mg, 1.912 mmol) were combined in anhydrous tetrahydrofuran (15 ml) and stirred for 60 min at 40 "C. Then a tetrahydrofuran solution (7 ml) of tert-butyl-2,2-dimethyl-4-(2-(3 -sulfamoylpyrazol-1-yl)ethoxy|pyrrolidine-1-carboxylate (550 mg, 1.416 mmol) and 1,8-diazabicyclo/|5.4.0undec-7ene (538.9 mg, 529.4 μl, 3.540 mmol). The reaction was heated at 40 "C for 14 h. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 75 95 ethyl acetate in hexane, obtaining tert-butyl 4-(2-III-C(2-chloro-6-(3-(2-P1-(trifluoromethyl)) as an off-white solid) cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-

Z carbonyl|Isulfamoyl|pyrazol-1 yl|ethoxy|-2,2-dimethylpyrrolidine-1-carboxylate (493 mg, 47 b).

MO-ER t/2 calc. 745.22723, found 746.29 (M--1)k; Holding time: 0.83 min. (Method of RH A).

Stage 3: 20,20-dimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10X6-thia-1,3,9, 14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12- pentane-8,10,10-trione (Compound 164)

OM z x m 2 M-KkM y: M x o- MM M si --- in TU

Kk va WHAT, -2 Sa y

CT -sh-

VosM

Tert-butyl 4-(2-3-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|pyrazol-1-yl| ethoxy|-2,2-dimethyl-pyrrolidine-1-carboxylate (467 mg, 0.6258 mmol) was dissolved in dichloromethane (10 mL) and hydrochloric acid (4.5 mL of 4 M in dioxane, 18.00 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. ) in a vial, purged with nitrogen, closed, heated to 140 C and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by reverse-phase preparative chromatography using a C18 column (3095-99 9o acetonitrile-water and 5 mM hydrochloric acid) to obtain 20,20-dimethyl-4 -(3-2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1 H-n in the form of a white solid irazol-1-yl)-17-oxa-10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2(7),3,5,11(22) ,12-pentane-8,10,10-trione (compound 164) (115 mg, 30 95). IN NMR (400 MHz, DMSO-ab) b 12.74 (5, 1H), 8.17 (a, U - 2.8 Hz, 1H), 7.96 (5, 1H), 7.69 (a, U - 68.2 Hz, 1H), 6.89 (a, 9 - 8.2 Hz, 2H), 6.08 (a, 9 - 2.8 Hz, 1H), 4.42 (I, U - 13.0 Hz, 1H), 4.38 - 4.07 (t, 5H), 3.88 (i, U - 11.4 Hz, 1H), 2.88 (5, 1H), 2.18 - 2.03 (t, 2H), 2.01 (a9, U - 11.5, 6.0 Hz, 1H), 1.78 1.9 - 9.1 Gu, 1H), 1.61 (Her , U 2 11.5 Hu, 1H), 1.54 (5, ЗН), 1.50 (5, ЗН), 1.01 - 0.92 (t, 2Н), 0.92 - 0.84 (t, 2Н). MO-IER t/2 calc. 609.1981, found 610.36 (M--1)k; Holding time: 2.03 min. (Method of RH B).

Stage 4: 20,20-dimethyl-4-(3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10X6-thia-1,3,9, 14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12- pentane-8,10,10-trione (enantiomer 1) (Compound 302) and 20,20-dimethyl-4-(3-(2-(1- (trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10A6-thia-1,3,9,14 ,22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 167)

Y M Y M Y M sany in Vnya

Racemic compound, 20,20-dimethyl-4-(3-2-P1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10X6-thia-1,3,9, 14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa- 2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound 164) (98 mg, 0 ,1591 mmol), was subjected to chiral preparative NCR to separate enantiomers. The following protocol was used

NCRC: SpigaIRak Av-3 (150 X 2.1 mm), Z μm; Mobile phase 35 "C: 30 95 acetonitrile:methanol (90:10), 70 95 carbon dioxide. The first eluted enantiomer was 20,20-dimethyl-4-(3-12-

P-"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10ХА6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa- 2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 302) (31 mg, 63 95); MO-IER tp/2 calc. 609.1981, found 610.32 (Me1)z; Retention time: 2.01 min (RC method). The second eluted enantiomer was 20,20-dimethyl-4-(3-12-(1-«"trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17-oxa-10A6-thia-1,3 ,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 167) (31 mg, 63 95); MO-IER tp/2 calc. 609.1981, found 610.28 (MA) k; Retention time: 2.0 min (method RH B).

Example 162: Preparation of 4-chloro-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12 -pentane-8,10,10-trione (enantiomer 1) of its 4-chloro-20,20-dimethyl-10Abthia-1,3,9,14,22-pentaazatetracycloi|16.2.1.111,14.02,7|docosa- 2 ,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2)

GI Kya o oo b oo s V M r

OS of Fort VO; epapioteg 1 epapioteg2

Stage 1: 4-chloro-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (enantiomer 1) (Compound E) and 4-chloro-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7| docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound E)

o oo chi M o ZM / o 5

M r -Z your li s In growth si a shchi si Mi code I si M ru epapioteg 1 epapioteg2

Racemic 4-chloro-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentaene-8,10,10-trione (498 mg) was subjected to chiral NCR chromatography. The following NCR protocol was used: SpPigaIRak

AB-N (250 X 21.2 mm), 5 μm; 35 "C, mobile phase: 18 95 acetonitrile:methanol (90:10), 82 95 carbon dioxide with a flow rate of 70 ml/min. The first eluted enantiomer was 4-chloro-20,20-dimethyl-10A6-thia-1, 3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7 |docosa- 2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (162 mg, 13 95). IN NMR (400 MHz, Spiogoitogt- a) 6 8.73 (5, 1H), 7.57 - 7.45 (t, 2H), 7.06 (a, U - 2.3 Hu, 1H), 6.49 (a, U - 7.8 Gu, 1H), 4.28 (a, 9 2 13.4, 3.3 Gu, 1H), 4.02 - 3.85 (t, 1H), 2.67 (5, 1H), 2.13 (ai, U - 11.4, 5.3 Hz, 2H), 2.08 - 1.98 (t, 1H), 1.92 (a, U - 15.4, 10.2 Hz, 2H), 1.77 - 1.70 (t, 1H), 1.54 (5, ЗН), 1.49 (5, ЗН), 1.44 (I, U - 12.3 Hu, 1H), 0.83 - 0.71 (t, 1H). MO-IER tp/2 calc. 423.1132, found 424.04 (M--1)k; Retention time: 166 min. (Method RH B). The second eluted enantiomer 4-chloro-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12- pentane-8,10,10-trione (enantiomer 2) (163 mg, 13 95). 1 H NMR (400 MHz, chloroform-a ) b 8.82 (5, 1H), 7.57 - 7.45 (t, 2H), 7.06 (a, U - 2.3 Hz, 1H), 6.49 (a, U - 7.8 Hz, 1H), 4.27 (a, U - 13.3, 3.4 Gu, 1H), 4.01 - 3.87 (t, 1H), 2.67 (5, 1H), 2.24 - 2.07 (t, 2H), 2.08 - 1.98 (t, 1H), 2.00 - 1.84 (t, 2H), 1.82 - 1.68 (t, 1H ), 1.54 (5, ZN), 1.49 (5, ZN), 1.44 (1, 9 - 12.3 Hz, 1H), 0.77 (Kf 9 - 18.68, 9.0 Gu, 1H). MO-IER t/27 calc. 423.1132, found 424.04 (M--1) same; -Retention time: 1.67 min (method RH B).

Example 163: Preparation of 4-I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14 22-pentaazatetracyclo|16.2.1.111, 14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 168) of its M R KY (c) - In ooo obli ditya mno 7 si ac m; HM - Mm-m s da bark: FI; code

Stage 1: 4-(3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02 ,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (compound 168) her M Ki Kui (9) hu p- Z m. OO z sOo child many 7 si M M MORE X - mm o r zyogtr

Solution of 4-chloro-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentaene-8,10,10-trione (75 mg, 0.1769 mmol), 1-(3,3-dimethylbutyl)imidazolidinyl-2-one (38 mg, 0.2232 mmol), tert-butoxide

Sodium chloride (27 mg, 0.2809 mmol) and chloro(2-di-tert-butylphosphino-2'4",6'-tri-isopropyl-1,1"-biphenyl)(2-(2-aminoethyl)phenyl) |palladium (II) (31 mg, 0.04760 mmol) in dioxane (2 mL) in a vial was degassed by purging with nitrogen for 2 min. Then the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 0.5 mL of acetic acid and filtered through a UMpaytap disc filter (Rigadises 25 TE) using a small amount of dimethyl sulfoxide, and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 50 95 to 99 95 mobile phase B in 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "C) to obtain 4-I3-(3,3-dimethylbutyl)- 2-oxoimidazolidin-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22 ),12-pentane-8,10,10-trione (compound 168) (24 mg, 24 95) as a white solid substances 1TN NMR (400 MHz, Spiogoitogit-a) b 8.38 (5, 1H), 7.55 (5, 2H), 7.46 (a, 9 - 2.3 Hu, 1H), 7.05 (a, U - 2.3 Hz, 1H), 4.35 (a, U - 11.7 Hz, 1H), 3.96 (a,

U - 36.5, 11.0 Hz, ZN), 3.46 (a, U - 68.4 Gu, 2H), 3.39 - 3.27 (t, 2H), 2.71 (v, 1H), 2.12 (5, 2H), 2.02 (5, 2H ), 1.92 (5, 1H), 1.72 (y, U - 8.8 Hz, 1H), 1.55 (5, ЗН), 1.49 (5, ЗН), 1.45 (аа, 9 - 10.1, 6.6 Hz, ЗН), 0.96 (5, 9Н), 0.79 (y, У - 9.7 Hz, 1Н). MO-IER t/; calculation 557.27844, found 558.17 (Ma-1)k; Holding time: 1.84 min. (Method of RH B).

Example 164: Preparation of 4-I(3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14 22-pentaazatetracyclo|16.2. 1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 169) (9)

Vg and 9)

Ver 1 Vier2 n vi Zier Z --i --i i nl nm --

MU about

Y M po

Mn sh-iY I Ver XX in sg p Ver 5 x uv U m: M. o i si M M M -- z y m M m Mm-k y hi

Stage 1: 4,4-dimethylpentanenitrile

1-bromo-3,3-dimethylbutane (25 g, 151.45 mmol) was slowly added to a suspension of sodium cyanide (8.17 g, 166.71 mmol) in dimethyl sulfoxide (80 mL) at 60 °C, maintaining the internal temperature between 55 °C and 65 °C. The reaction mixture was heated at 70 °C for 90 min, then cooled to room temperature. The reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (3 x 150 mL). The organic layers of were combined, washed with 5 N hydrochloric acid (75 ml) and water (75 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 4,4-dimethylpentanitrile (17.82 g, 89 95) in the form of pure oil. The crude material was used directly in the next stage without additional purification. TN NMR (300 MHz, SOSIS) ppt 0.93 (5, 9Н), 1.56-1.67 (t, 2Н), 2.28 (ai, U-8.8, 7.3 Hz, 2Н ).

Stage 2: 4,4-dimethylpentanal and x 7 H -- the same

Diisobutylaluminum hydride (226 mL of 1 M in dichloromethane, 226.00 mmol) was added to a solution of 4,4-dimethylpentanenitrile (16.75 g, 150.65 mmol) in dichloromethane (560 mL) at 0 "C. The reaction mixture was stirred at 0 "C for 90 min, then quenched with 3 M hydrochloric acid.

The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with 10 95 hydrochloric acid, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 4,4-dimethylpentanal

Zo (16.23 g, 94 Fo) in the form of a yellow oil. The crude material was used in the next step without any additional purification. 1H NMR (300 MHz, SOSIZ) rrit 0.90 (5, 9H), 1.46-1.61 (t, 2H), 2.40 (4, 9U-8.1, 1.9 Hz, 2H), 9.78 (I, 9U-1.9 Hz, 1H) .

Stage 3: tert-butyl-M-(2-(4,4-dimethylpentylamino)ethylcarbamate (o) (c) (c) c

4,4-dimethylpentanal (15.2 g, 133.12 mmol) was added to a solution of tert-butyl M-(2-aminoethyl)carbamate (20.948 g, 20, 7 mL, 130.75 mmol) in methanol (300 mL), and the reaction mixture was stirred at room temperature for 1 hour. After cooling the reaction mixture to 0 "C, sodium borohydride (5.2 g, 137.45 mmol) was slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure.

The residue was dissolved in ethyl acetate (300 ml) and washed with a saturated aqueous solution of sodium bicarbonate (2 x 300 ml) and brine (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl M-(2- (4,4-dimethylpentylamino)ethyl carbamate (21.83 g, 65 95) as a yellow oil. The crude material was used in the next step without any further purification. MO-IER n/2 calcd. 258.2307, found 259, 3 (MAT) k, holding time: 1.39 min (Method RH I).

Stage 4: 1-(4,4-dimethylpentyl)imidazolidinyl-2-one and D

KO I kt chn

Solid potassium tert-butoxide (28.6 g, 254.87 mmol) was added to a solution of tert-butyl N-(2-(4,4-dimethylpentylamino)ethylcarbamate (21.83 g, 84.481 mmol) in tetrahydrofuran (260 mL) and the reaction mixture was heated at 60 C for 3 hours. After cooling to room temperature, the reaction mixture was acidified to pH 1-2 with aqueous hydrochloric acid (1 M) and concentrated under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 x 250 mL), the organic layers were combined, washed with saline (2 x 200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure.

The residue was purified by silica gel chromatography using a gradient of 0 o to 10 95 methanol in ethyl acetate to give 1-(4,4-dimethylpentyl)imidazolidinyl-2-one (7.36 g, 45 95) as an off-white solid color TN NMR (300 MHz, DMSO-ab) ppt 0.84 (5, 9H), 1.02-1.15 (t, 2H), 1.28-1.43 (t, 2H), 2.96 (I, 9U-7.2 Hz, 2H), 3.14- 3.22 (t, 2H), 3.23-3.31 (t, 2H), 6.20 (Bg. 5., 1H). MO-IER t/: calc. 184.1576, found 185.3 (M--1)k; retention time: 2.34 min. (The method of RH N).

Stage 5: 4-(3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl|-20,20-dimethyl-10Abthia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02 ,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (compound 169) se Х ХО (9) ху Гай Х ху re: m 9 H in

Zh k s | M m 7 --- M / 7

Ko - shcha Ko KON la

Solution of 4-chloro-20,20-dimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentaene-8,10,10-trione (30 mg, 0.07077 mmol), 1-(4,4-dimethylpentyl)imidazolidinyl-2-one (16 mg, 0.08683 mmol), tert-

From sodium butoxide (12 mg, 0.1249 mmol) and chloro(2-di-tert-butylphosphino-2'24"6'-tri-isopropyl-1,1"-biphenyl)|(2-(2-aminoethyl) phenyl|palladium(II) (14 mg, 0.02150 mmol) in dioxane (2 mL) in a vial was degassed by purging with nitrogen for 2 min. The mixture was stirred at room temperature for about 1 h. The reaction mixture was quenched with 0.5 mL of acetic acid and was filtered through a UMpaytap disc filter (Rigadies 25 TE) using a small amount of dimethyl sulfoxide, and the filtrate was purified by reversed-phase HPLC-MS using a double gradient from 50 90 to 99 95 mobile phase B in 15.0 min (mobile phase

A-water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25 "C) to obtain 4-(3-(44- dimethylpentyl)-2-oxoimidazolidin-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2,4,6, 11(22),12-pentane-8,10,10-trione (compound 169) (6.8 mg, 16 95) as an off-white solid. 1H NMR (400 MHz, Spiogoitogt-a) b 8.54 ( 5, 1H), 7.54 (5, 2H), 7.46 (a, U - 2.2 Hz, 1H), 7.05 (a, U - 2.1 Gu, 1H), 4.35 (y, U - 13.2 Hz, 1H), 4.09 - 3.85 (t, ЗН), 3.46 (a, y - 8.7 Gu, 2Н), 3.27 (Y, У - 7.3 Hz, 2Н), 2.71 (5, 1Н), 2.11 (5, ЗН), 1.99 - 1.85 (t ) 1.17 (t, 2H), 0.88 (5, 8H), 0.75 (a, U - 19.6 Hz, 2H). MO-IER t/ cal. 571.29407, found 572.3 (М-А1)хж; Retention time: 2.02 min. (Method of RH B).

Example 165: Preparation of /(145)-8-I3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 170) and (145 )-8-I3-(3,3-

dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22) ,5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 171) c)

M

HER M HER M Y M dune SU diaziegeoteg 1 diaziegeoteg 2

Stage 1: 3-(3,3-dimethylbutoxy)pyrrolidin-2-one (c) (c) he r: . In dO

To a stirred solution of 3,3-dimethylbutan-1-ol (540 mg, 5.285 mmol) in anhydrous tetrahydrofuran (20 mL) was added (bis(trimethylsilyl)amino|potassium (10.6 mL of 0.5 M in toluene, 5.300 mmol) at ambient temperature under a nitrogen atmosphere. The milky reaction mixture was stirred for 30 min, then a solution of 3-bromopyrrolidin-2-one (830 mg, 4.808 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise at 0 "C (ice bath ). The reaction mixture was allowed to gradually warm to ambient temperature overnight (18 h). The reaction mixture was acidified with 1 M aqueous hydrochloric acid (1.5 mL) and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed brine (15 ml). The organic part was dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure to give a brown crude material. The crude product was purified by chromatography on silica gel (0395-1095 methanol in dichloromethane gradient) with obtaining /3-(3,3-dimethylbutoxy)pyrrolidin-2-one (143 mg, 16 95) as a white solid. MO-IER t/: calc. 185.14159, found 186.2 (M.-1) same; retention time: 0.95 min. (Method of RH B).

Stage 2: (145)-8-I3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (c) M (c) oy (c) xx m. with m? with

MN s M M y -ya o M l me

Kk (and Uch shdd

(145)-8-chloro-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23) was introduced into the vial. 5,7,9,19,21-hexane-2,2,4-trione (100 mg, 0.2222 mmol), 3-(3,3-dimethylbutoxy)pyrrolidin-2-one (50 mg, 0.2699 mmol), cesium carbonate (290 mg, 0.8901 mmol), 4,5-bisidiphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.03457 mmol)

Zo (xanthophos) and dry dioxane (2 ml) in the specified order. Nitrogen was blown through the heterogeneous mixture for 3 min. Rag(ara)Z (20 mg, 0.02184 mmol) was then added under nitrogen and the vial was purged with nitrogen for another 2 min, then sealed under nitrogen. The mixture was stirred at 115°C for 15 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (130 μL, 2.286 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (3.0 mL) and filtered through M/paytap syringe disc filter with 0.45 µm PTFE The sample was purified by preparative reversed-phase HPLC-MS (30-99 95 gradient acetonitrile in water over 15 min (hydrochloric acid as modifier).

Fractions of the desired product were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (145)-8-I3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia - 3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4- -rione (27 mg, 20 95) in the form of an off-white solid mixture of diastereomers. TN NMR (4600 MHz, Meipapo!-a4) b 7.78 (ad, 9 - 8.4, 2.1 Gu, 1n), 7.60 (da, 9 - 8.4, 4.3 Hz, 1n), 7.53 (aa,

У - 8.5, 7.2 Hz, 1Н), 7.16 (а, у - 7.2, 1.0 Гу, 1Н), 6.65 (а, У - 8.5 Hz, 1Н), 4.25 (а, У - 12.8, 8.0 Hz, 1Н), 4.20 - 3.99 (t, 2H), 3.97 - 3.76 (t, 2H), 3.74 - 3.65 (t, 1H), 3.03 (y, U - 13.68 Hu, 1H), 2.86 (y,

U - 9.9 Hz, 1H), 2.56 - 2.44 (t, 1H), 2.17 (5, 1H), 2.04 - 1.93 (t, 1H), 1.84 (ai, U - 11.7, 5.7 Hz, 2H), 1.63 (Br , 6H), 1.61 - 1.55 (t, 4H), 1.54 (5, 2H), 1.44 (Y, 9) - 11.6 Hz, 1H), 0.95 (5, 9H). MO-IER t/27 calc. 598.29376, found 651.4 (M.-1)k; Holding time: 2.04 min. (Method of RH B).

Stage C: (145)-8-N3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 170) and (145) -8-I(3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|I-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111 ,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 171)

HER M HER M HER M all of S

Racemic diastereomeric (145)-8-I3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2А6б-thia-3,9,11,18,23-pentaazatetracycloi|17.3 .1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione was subjected to chiral NKR chromatography.

The following NKRH protocol was used: StpigaISe! 0-H (250 X 10 mm), 5 μm; mobile phase: 20 95 acetonitrile:methanol (90:10; no modifier), 80 95 carbon dioxide at a flow rate of 10 mL/min to provide as the first eluted diastereomer (145)-8-I3-(3,3-dimethylbutoxy )-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (compound 170) (11 mg, 8 95); IN NMR (400 MHz, DMSO-ab) b 12.43 (5, 1H), 7.70 (a,

U - 8.3 Gu, 1H), 7.57 (Y, U - 7.8 Hz, 1H), 7.51 (a, y - 8.3 Hz, 1H), 7.04 (a, 9 - 7.2 Hz, 1H), 6.96 (5, 1H) . 9 - 10.5, 7.6 Hz, 1H), 3.60 (4, 9 - 9.2, 7.2 Hz, 1H), 3.20 - 3.03 (t, 1H), 2.94 (y, U - 13.4 Hz,

Zo 1H), 2.77 - 2.63 (t, 1H), 2.46 - 2.37 (t, 1H), 2.18 - 2.04 (t, 1H), 1.91 (ad, U - 12.6, 8.4 Hz, 1H), 1.82 (ad, y - 11.6, 5.2 Gu, 1H), 1.80 - 1.68 (t, 1H), 1.64 - 1.57 (t, 2H), 1.57 (5, ЗН), 1.52 - 1.48 (t, 2Н), 1.46 (5, ЗН), 1.34 - 1.26 (t, 1H), 1.24 (5, 1H), 0.91 (a, 9U - 0.9 Gu, 9H), MO-IER t/2 calc. 598.29376, 599.4 (Ma-1) found; Holding time: 2.21 min. (Method LC B) and as the second eluted diastereomer, (145)-8-13-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl|-12,12-dimethyl-2A6-thia-3,9 ,11,18,23-pentaazatetracyclo (17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (Compound 171) (10 mg, 7 U); "YAN NMR (400 MHz, DMSO-4a6) b 12.41 (5, 1H), 7.70 (a, U -8.4 Hz, 1H), 7.57 (9 - 7.9 Hz, 1H), 7.53 (j,

U - 8.4 Gu, 1H), 7.04 (a, y - 7.2 Hz, 1H), 6.96 (5, 1H), 6.70 (a, 7 - 8.5 Hz, 1H), 4.28, 9 - 8.3 Hz, 1H), 3.97 - 3.92 (t, 1H), 3.92 - 3.89 (t, 1H), 3.89 - 3.84 (t, 1H), 3.77 (a, U - 10.2, 7.5 Gu, 1H), 3.59 (aa,

U same 9.3, 7.7, 6.7 Hu, 1H), 3.16 - 3.03 (t, 1H), 2.94 (y, U 2 13.3 Hu, 1H), 2.74 - 2.64 (t, 1H), 2.48 - 2.39 (t, 1H) , 2.20 - 2.02 (t, 1H), 1.93 - 1.85 (t, 1H), 1.84 - 1.79 (t, 1H), 1.79 - 1.69 (t, 1H), 1.63 - 1.57 (t, 2H), 1.57 (5, ЗН), 1.52 - 1.47 (t, 2Н), 1.46 (5, ЗН), 1.29 (y, U 2 12.4 Hu, 1Н), 1.24 (5, 1Н), 0.91 (5, 9Н). MO-IER t/2 calc. 598.29376, found 599.4 (May1)-; Retention time: 2.18 min (method RH B).

Example 166: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1 ) (Compound 172) and (145)-12,12-dimethyl-8-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 173)

HER M Y 5 HER M o y M y o HU M y o y M he

Stage 1: (145)-12,12-dimethyl-8-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1 ) (Compound 172) and (145)-12,12-dimethyl-8-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) (Compound 173)

HER M HER U HER MU o sh M xx o sh M sh o U M t

A mixture of diastereomers (145)-12,12-dimethyl-8-(2-oxo-3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9,11,18 ,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (dihydrochloride salt) (31 mg) were subjected to chiral purification by NCR. The used purification method of NKRK used a SpigaiSe column! 0О-Н (250 x 10 mm), 5 μm; mobile phase: 2095 acetonitrile:methanol (90:10; without modifier), 80 95 carbon dioxide; consumption: 10 ml/min; Sample concentration: "- 24 mg/ml in a mixture of acetonitrile: methanol: dimethylsulfoxide (85:9:6); injection volume: 70 μl; pressure: 100 bar. The first eluted diastereomer was (145)-12,12-dimethyl-8-(2-oxo-3-12-[P1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9, 11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 1) (Compound 172) (7 mg, 5 9c). MO-IER t/2 calc. 650.2498, found 651.4 (Ma1)f; retention time: 2.09 min. (Method of RH B). The second eluted diastereomer was (145)-12,12-dimethyl-8-(2-oxo-3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-2A6-thia-3,9,11 ,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (diastereomer 2) ( Compound 173) (7 mg, 5 90). MO-IER t/72 calc. 650.2498, found 651.4 (M.-1)khk; retention time: 2.09 min. (Method of RH B).

Example 167: Preparation of 20,20-dimethyl-4-(2-oxo-3-13-11-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-10Abthia-1,3,9,14,22- pentaazatetracyclo |16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 1) (compound 181) and 20,20-dimethyl-4- (2-oxo-3-13-11-

Zo (trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22), 12-pentane-8,10,10-trione (diastereomer 2) (Compound 182) (9) o M r po, | OesholE: and M- M ---e

SIM M epapioteg 2 (9)

Oi M o i ah 9 zu "15. shi

M We M shk; М М M ШЭ вс г diaziegeoteg 1 diazeivgeoteg 2

Stage 1: 20,20-dimethyl-4-(2-oxo-3-13-1/1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-

8,10,10-trione (diastereomer 1) (Compound 181) and 00 20,20-dimethyl-4-(2-oxo-3-13-|1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl) -10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 2 ) (Compound 182) (9) o M r y Mi -e8--

SIM M epapioteg 2 (9)

OO M o sh m h o y: M Bh 15. dO

M 2 M mk M M M M vs g diaziegeoteg 1 diaziegeoteg 2

4-chloro-20,20-dimethyl-10А6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22) was introduced into the vial 12-Pentane-8,10,10-trione (enantiomer 2) (40 mg, 0.09436 mmol), 3-I3-/1-trifluoromethyl)cyclopropyl|propyl|pyrrolidin-2-one (27 mg, 0, 1148 mmol), cesium carbonate (110 mg, 0.3376 mmol), 4,5-bisb(idiphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.01555 mmol) (xanthphos) and dry dioxane (2 mL) in in the specified order.

Nitrogen was bubbled through the heterogeneous mixture for 2 min. Then nitrogen was added in the atmosphere

Rag(ara)z (9 mg, 0.009960 mmol) and nitrogen was bubbled through the reaction mixture for another 2 minutes, and then the mixture was blocked under a nitrogen atmosphere. The mixture was stirred at 115 °C for hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μL, 0.8792 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through 0.45 μm PTFE syringe disc filter UUPytap. The sample was purified by preparative reversed-phase HPLC-MS (30-99 95 acetonitrile in water for 15 min (hydrochloric acid as a modifier)). Fractions of the desired product were combined and concentrated at under reduced pressure, and the residue was dissolved in ethyl acetate (25 ml) and successively washed with saturated aqueous sodium bicarbonate (2 x 10 ml) and saline (10 ml).

The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 20,20-dimethyl-4-(2-oxo-3-13-(1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)- 10ХА6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (41 mg 70 95) in the form of an off-white solid mixture of diastereomers, which was subjected to chiral purification

NKRH using a SpPiga(Se! 0.)-3H column (250 x 10 mm), 5 μm; mobile phase: 20 95 acetonitrile:methanol (90:10; without modifier), 8095 carbon dioxide; flow: 10 ml/min; concentration: « 24 mg/ml in acetonitrile: methanol: dimethyl sulfoxide (81:9:10); injection volume: 70 μl; pressure: 100 bar; wavelength: 242 nm. The first eluted diastereomer was 20,20-dimethyl-4-(2-oxo-3-13-/1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-10A6-thia-1,3,9,14, 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 1) (Compound 181) (11 mg, 18,965 ). MO-IER t/2 calc. 622.2549, found 623.4 (MA1) zhk; retention time: 2.18 min. (Method of RH B). The second eluted diastereomer was 20,20-dimethyl-4-(2-oxo-3-13-/1-(trifluoromethyl)cyclopropyl|propyl)pyrrolidin-1-yl)-10A6-thia-1,3,9,14, 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 2) (Compound 182) (10 mg, 17,965 ). MO-IER t/2 calc. 622.2549, found 623.4 (MA) k; retention time: 2.19 min. (Method of RH B).

Example 168: Preparation of 20,20-dimethyl-4-(2-oxo-3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10A6bthia-1,3,9,14,22- pentaazatetracyclo |16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 183), 20,20-dimethyl-4-(2-oxo -3-(2-/1-("trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10Abthia-1,3,9,14,22-pentaazatetracyclo]16.2.1.111,14.02,7|docosa-2, 4,6,11(22),12-pentane-8,10,10-trione (diastereomer 1) (Compound 191) and 20,20-dimethyl-4-(2-oxo-3-12-(1-

(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10A6bthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22),12 -pentane-8,10,10-trione (diastereomer 2) (Compound 192)

BK se, epapioteg 2

Y M Y M o eh M o y: M Zh o M M M (o) M M M diaziegegeoteg 1 diaziegegeoteg 2

Stage 1: 20,20-dimethyl-4-(2-oxo-3-42-P1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10Abthia-1,3,9,14,22-pentaazatetracyclo/ 16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 183) 9 9

T.k si schu o M M la

CT scan Epapioteg 2

4-chloro-20,20-dimethyl-10А6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22) was introduced into the vial 12-Pentane-8,10,10-trione (enantiomer 2) (40 mg, 0.09436 mmol), 3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|pyrrolidin-2-one (23 mg, 0, 09696 mmol), cesium carbonate (102 mg, 0.3131 mmol), 4,5-bisb(idiphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01383 mmol) (xanthphos) and dry dioxane (1.5 mL ) in the specified order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Then, Ra(aba)zZ (8 mg, 0.008853 mmol) was added under nitrogen and nitrogen was bubbled through the reaction mixture for another 2 min, then sealed under nitrogen. The mixture was stirred at 115 °C for 15 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μL, 0.8792 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through disk filter of the MUpipetap syringe with PTFE 0.45 μm azo was purified using preparative reversed-phase HPLC-MS (30-99 95 acetonitrile in water for 15 min., hydrochloric acid as a modifier). Fractions of the desired product were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25 ml) and washed successively with saturated aqueous sodium bicarbonate (2 x 10 ml) and saline (10 ml).

The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 20,20-dimethyl-4-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl) ( compound 183) (41 mg, 74 95) as an off-white solid. TN NMR (400 MHz, MeShapo!1-a«) b

Zo 7.19 (a, 9 - 2.3 Hz, 1H), 7.64 (ai, U - 8.4, 2.1 Hz, 1H), 7.61 - 7.54 (t, 1H), 6.91 (da, U - 2.4,1.1 Gu, 1H), 4.91 - 4.21 (t, 2H), 4.16 (ada, U - 11.8, 8.8, 3.2 Hu, 1H), 4.12 - 4.00 (t, 1H), 3.96 (d, U - 7.5 Hz, 1H), 3.90 - 3.72 ( t, 2H), 2.83 - 2.73 (t, 1H), 2.55 - 2.43 (t, 1H), 2.23 - 2.08 (t, 2H), 2.02 - 1.87 (t, 6H), 1.77 (da, U - 11.9, 5.4 Hz, 1Н), 1.57 (5, ЗН), 1.50 (5, ЗН), 1.39 (I, У - 12.2 Hz, 1Н), 0.96 - 0.90 (t, 2Н), 0.84 - 0.76 (t, 2Н), 0.76 - 0.68 (t, 1Н). MO-IER ip/2 calc. 624.2342, found 625.4 (MA) k;

Holding time: 2.05 min. (Method of RH B).

Stage 2: 20,20-dimethyl-4-(2-oxo-3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 1) (Compound 191) and 00 20,20-dimethyl- 4-(2-oxo-3-(2-|1- (trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10A6bthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 2) (Compound 192)

oh oh

ХМ сх ГТ 0 M What

BK c) (c) B ZM /Y

Sh 7 th: M o | i TU and about | 7 m U o M M M sh o M M More diaziegeoteg 1 diaziegeoteg 2 20,20-dimethyl-4-(2-oxo-3-2-|11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)- 10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 183 ) were subjected to chiral NCR using a SpigaIRak Is column (250 x 10 mm), 5 μm; mobile phase: 42 95 acetonitrile:methanol (90:10; without modifier), 58 95 carbon dioxide; flow: 70 ml/min; concentration: I 24 mg/ml in a mixture of acetonitrile:methanol (90:10, without modifier); injection volume: 70 μl; pressure: 100 bar. The first eluted diastereomer was 20,20-dimethyl-4-(2-oxo-3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10X6-thia-1,3,9,14 ,22-pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 1) (Compound 191) (13.6 mg , 24 9c). MO-IER t/72 calc. 624.2342, found 625.4 (MA1) zhk; retention time: 1.87 min. (Method of RH B). The second eluted diastereomer was 20,20-dimethyl-4-(2-oxo-3-12-P1-(trifluoromethyl)cyclopropyl|ethoxy)pyrrolidin-1-yl)-10X6-thia-1,3,9,14,22 -pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (diastereomer 2) (Compound 192) (13.5 mg, 24 95). MO-IER t/2 calc. 624.2342, found 625.4 (Ma1) xx; retention time: 1.88 min. (Method of RH B).

Example 169: Preparation of 4-I(3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-20,20-dimethyl-10A6-thia-1,3,9,14, 22-pentaazatetracycloi|16.2 .1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 184)

OO oo GI KU (c) M s V et i to 1 g epapioteg 1

Stage 1: 4-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-20,20-dimethyl-10Abthia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02, 7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (compound 184) - and V | 2 Y si M shcha shk M M la epapioteg 1

4-chloro-20,20-dimethyl-10А6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2,4,6,11(22) was introduced into the vial 12-pentan-8,10,10-trione (enantiomer 1) (11 mg, 0.02595 mmol), 3-(3,3-dimethylbutyl)pyrrolidin-2-one (8 mg, 0.04726 mmol), carbonate cesium (32 mg, 0.09821 mmol), 4,5-bis(idiphenylphosphino)-9,9-dimethylxanthene (3 mg, 0.005185 mmol) (xanthphos), and dry dioxane (0.8 mL) in the indicated order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Then Rag(aura)Z (Z mg, 0.003320 mmol) was added under a nitrogen atmosphere and nitrogen was bubbled through the mixture for another 2 minutes and the mixture was closed in the atmosphere

From nitrogen. The mixture was stirred at 115 °C for 13 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0 mL) and filtered through M/paytap syringe disc filter with 0.45 μm PTFE. The sample was purified by preparative reversed-phase HPLC-MS (30-99 95 acetonitrile in water for 15 min (hydrochloric acid as a modifier)). Fractions of the desired product were combined and concentrated under reduced pressure to obtain 4-I3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl|-20,20-dimethyl-10Ab6-thia-1,3,9,14,22- pentaazatetracyclo|16.2 .1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (compound 184) (7.5 mg, 51 95) as a pale yellow solid substances. 1H NMR (400 MHz, Meiapo!1-a4) b 7.18 (a, 9 - 2.5 Hz, 1H), 7.67 - 7.60 (t, 1H), 7.56 (aa, U - 8.5, 7.0 Gu, 1H), 6.91 (y, - 2.4 Hz, 1H), 4.33 - 4.22 (t, 1H), 4.20 - 4.11 (t, 1H), 4.10 - 3.97 (t, 1H), 3.96 - 3.78 (t, 1H), 2.83 - 2.73 (t, 1H), 2.62 (aa, o - 13.7, 9.4, 5.0 Hu, 1H), 2.31 (d, U - 9.0 Gu, 1H), 2.21 - 2.08 (t, 2H), 2.04 - 1.84 (t, 4H), 1.81 - 1.69 (t, 2H), 1.57 (5, ЗН), 1.51 (5, ЗН), 1.39 (Y, U - 12.4 Gu, 2H), 1.33 - 1.27 (t, 2H), 0.92 (v, 9H), 0.79 - 0.66 (t, 1H). MO-IER ip/2 calc. 556.2832, found 557.5 (M'-1) kg; retention time: 2.23 min. (Method of RH B).

Example 170: Preparation of (18K)-4-I3-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6-thia- 1,3,9,14,22-pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 186 ) about M TO

I M SI I B; If I were; - zi tO Y M Her M

Stage 1: tert-butyl 4-I3-I(3-(2-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl |sulfamoyl|pyrazol-1-yl|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

MM 2 o (c) eeu xx ri: m r o- TM M si

She ZV Me. --o o va 2 sh in; IN; 2-chloro-6-I3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (400 mg, 1.112 mmol) and carbonyldiimidazole (273.5 mg , 1.687 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at room temperature. tert-Butyl-2,2-dimethyl-4-N3-(3-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (429.5 mg, 1.111 mmol) was then added, followed by 1,8-diazabicyclo/ 5.4.F)undec-7-ene (430.8 mg, 2.830 mmol), and the reaction mixture was stirred at room temperature for 1 h, then heated to 50 °C and stirred overnight. The reaction mixture was diluted with ethyl acetate and

Zo was washed with a saturated aqueous solution of sodium bicarbonate, and then with a saline solution.

The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient of 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 4-I3-(3- (2g-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|pyrazol-1-yl|Ipropyl|-2,2 -dimethylpyrrolidine-1-carboxylate (350 mg, 43 95). 1TH NMR (400 MHz, DMSO-46) 5 8.34 (5, 1H), 8.08 (y, 9 - 8.2 Hz, 1H), 7.77 (5, 1H) , 7.62 (y, 9 - 8.3

Hz, 1TN), 6.71 - 6.49 (t, 1Н), 6.10 (а, У - 2.8 Hz, 1Н), 4.23 (5, 2Н), 4.13 (5, 2Н), 3.52 (5, 1Н), 2.73 (y , 9 - 6.0 Hz, 1H), 2.08 (a, U - 6.7 Hz, 1H), 1.81 (d, U - 6.6 Hz, 5H), 1.47 (I, U - 6.5 Hz, 1H), 1.40 - 1.21 (t ,

18H), 0.83 (y, 9 - 2.0 Hz, 4H), 0.66 - 0.60 (t, 2H), 0.52 - 0.46 (t, 2H). MO-IER t/2 calc. 127.2919, found 728.1 (M--1) k; retention time: 0.92 min. (Method of RH A).

Stage 2: 2-chloro-M-(1-(3-(5,5-dimethylpyrrolidin-3-yl)propyl|pyrazol-3-yl|isulfonyl-6-|3-(2- dispiro|2.0.2.1 |heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide and M c; c;

Tert-butyl 4-I(3-I3-Ce-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl|isosulfamoyl|pyrazole -1-yl|Ipropyl|-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 0.4806 mmol) was dissolved in dichloromethane (1.527 mL) and trifluoroacetic acid (2.192 g, 1.481 mL, 19.22 mmol) was added to the mixture ), and the resulting mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure and dissolved in saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. (CAUTION, the solubility of the product in ethyl acetate under these conditions is low, the addition of some methanol helps , required for evaporation of the organic layer without the use of a solid drying agent).

The organic layer was concentrated on a rotary evaporator followed by drying in vacuo to give 2-chloro-N-(1-N3-(5,5-dimethylpyrrolidin-3-yl)/propyl|pyrazol-3-yl|!sulfonyl-6-| 3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (301.9 mg, 100 95) as an off-white solid, which was used directly in the next stage. 1N

NMR (400 MHz, Spiogottt-a) b 8.28 (a, 9U - 2.8 Hz, 1H), 8.21 (a, U - 8.3 Hu, 1H), 7.61 (a, U - 8.3 Hz, 1H), 7.44 (5, 1H), 6.67 (5, 1H), 5.88 (9.9 - 2.8 Hz, 1H), 4.22 (1, 9 - 6.68 Gu, 2H), 4.17 (5, 2H), 3.55 (5, 1H), 3.03 ( 5, 1H), 2.23 (5, 1H), 1.68 (y, U - 6.7 Gu, 2H), 1.83 (5, ЗН), 1.48 (5, 1H), 1.46 - 1.35 (t, 5H), 1.35 - 1.24 (t, 4H), 0.84 (I, U - 1.9 Hz, 4H), 0.63 (a, 9 - 1.6 Hu, 2H), 0.51 (a, 9 - 1.1 Hu, 2H).

Stage 3: 4-13-(2-Idispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6-thia-1,3,9, 14,22-pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione

Y M o ss y, U lyn ah shk | y y In 2 or

2-chloro-M-(1-(3-(5,5-dimethylpyrrolidin-3-yl)propyl|pyrazol-3-yl|isulfonyl-6-I(3-(2-dispiro|2.0.2.1 |heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-Z-carboxamide (310 mg, 0.4935 mmol), potassium carbonate (341.1 mg, 2.468 mmol), cesium fluoride (112.8 mg, 0, 7426 mmol), molecular sieves Z A and dimethyl sulfoxide (9.3 ml) in a vial that was purged with nitrogen, closed with a lid, heated to 155 "C and stirred for 20 hours. Then the mixture was cooled to room temperature

From the temperature and filtered, then diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel using a gradient from 100 95 hexanes to 10095 ethyl acetate (the product eluted after reaching 100 95 ethyl acetate) to give 4-IZ-( 2-di-dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3,9,14,22- pentaazatetracyclo/16.2 .1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (117 mg, 95). IN NMR (400 MHz, Spiogotogt-4) b 8.37 (5, 1H), 8.16 (a, U - 2.68 Hz, 1H), 7.68 (a, U - 8.3 Gu, 1H), 7.48 (a, U - 2.3 Hz , 1H), 7.26 (5, 1H), 7.07 (a, U - 2.3 Hz, 1H), 7.02 (a, U - 8.3 Hz, 1H), 5.86 (a, y - 2.8 Hz, 1H), 4.36 (y . 2H), 2.08 - 1.93 (t, ZN), 1.89 (a, U - 6.7 Hz, 2H), 1.76 (da, U - 11.9, 5.3 Gu, 1H),

1.59 (5, ЗН), 1.55 (5, 5Н), 0.85 (d, У - 2.0 Hz, 4Н), 0.64 (а, 9 - 1.7 Hz, 2Н), 0.51 (а, У - 1.2 Hz, 2Н).

MO-ER t/2 calc. 591.26276, found 592.4 (M--1); Holding time: 2.37 min. (Method of RH B).

Stage 4: (18K)-4-I3-(2-(dispiro(2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10X6-thia-1,3 ,9,14 22-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (Compound 186)

Y B Ii M - ra 4-IZ-(2-idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-20,20-dimethyl-10A6-thia-1, 3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (103 mg 0.1741 mmol) subjected to chiral separation by means of NKR chromatography using Spigaibak AB-N (250 X 10 mm, particle size 5 μm) with a mobile phase of 34 95 acetonitrile/methanol (90:10)/66 95 carbon dioxide at 10 ml/min for 8 ,0 min (injection volume - 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10)), which gives (18K)-4-I3-(2--dispiro|2.0) as the first eluted enantiomer. 2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-20,20-dimethyl-10X6-thia-1,3,9,14,22-pentaazatetracycloi16.2.1.111,14.02,7|docosa-2 ,4,6,11(22),12-pentane-8,10,10-trione (compound 186) (40.8 mg, 7990). MO-IER t/2 calc. 591.26276, found 593.1 (М--1)хк; retention time: 2.3 min. (Method of RH B).

Example 171: Preparation of (14K)-12,12-dimethyl-8-(3T3-P-trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11 ,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 190) KhM/Y xx he in M. 2 vivr1i

Meme We si t

Z i VosM MN vs -K I

Ii M o oo vh M z M m s ! d and fri 5-7 M si Vira po | r N I r « y Shi tsk In Z ys M i scho vs d-- MN

XXI ps

Stage 1: 2-chloro-M-(6-(3-(5,5-dimethylpyrrolidin-3-yl)/propylamino|-2-pyridyl|sulfonyl|-6-(3-

13-P-"trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide

I M YO in U uv hu 5 on | | N

Seam Y and -0-- 5-0 M si |v

With i i i d- In es

From a 50 mL flask charged with carbonyldiimidazole (216 mg, 1.332 mmol) and 2-chloro-6-I3-I|3-

N-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (520 mg, 1.334 mmol) was pumped off with nitrogen, then backfilled with nitrogen. Tetrahydrofuran (8 ml) was added and the mixture was stirred at 50 "C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1 -carboxylate (500 mg, 1.212

2 mmol) and 1,8-diazabicyclo|5.4.Fundec-7-ene (555 mg, 3.646 mmol) in tetrahydrofuran (3 mL) and the mixture was stirred overnight at 50 "C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, concentrated and purified by chromatography on silica gel (from 0 95 to 50 956 ethyl acetate in hexane) to obtain some pure fractions. with hydrochloric acid modifier The pure fractions from the silica gel column and the preparative HPLC column were combined to give the acyl sulfonamide intermediate, which was dissolved in dioxane (5 mL) and then treated with dioxane solution of hydrochloric acid (2 mL of 6 M, 12.00 mmol ) and then stirred at room temperature for 2 h. The mixture was evaporated with oil and the residue was quenched with aqueous sodium bicarbonate. The white precipitate of the product was filtered and washed with ethyl acetate. The aqueous phase was further extracted with ethyl acetate. O The organic extract was dried over sodium sulfate, filtered and evaporated, obtaining after drying the oil 2-chloro-M-I((6-13-(5,5-dimethylpyrrolidin-3-yl)/upropylamino)|-2-pyridyl| sulfonyl|-6-(3-3-[1-trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxamide (343 mg, 41 95). MO-IER t/7 calc. 683.2268, found 684.32 (Ma1)f; retention time: 0.65 min. (Method of RH A).

Stage 2: (14K)-12,12-dimethyl-8-(3-13-11-"trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11, 18,23-pentaazatetracyclo|17.3.1.111,14.05,10|htetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (compound 190)

PO o'clock | M s iv /ofi | V v -0-Io M b M ikh "Z i sh- sh MN Z i M M y, ts d- Mn

Cesium fluoride (160 mg, 1.053 mmol), potassium carbonate (360 mg, 2.605 mmol), and 4A molecular sieves (600 mg) were combined in a 5 mL vial, and the vial was evacuated and then re-injected with nitrogen. Next, a solution of 2-chloro-M-(6-(3-(5,5-dimethylpyrrolidin-3-yl)upropylamino|-2-pyridyl|sulfonyl)|-6-(3-I3-(1-trifluoromethyl) cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carboxamide (350 mg, 0.5116 b mmol) in dimethyl sulfoxide (5 mL), and the mixture was stirred at 150 °C overnight. The mixture was filtered and purified by preparative reversed-phase HPLC (C18): 1 95-99 95 acetonitrile in a water/hydrochloric acid modifier to give the racemic product.The racemate was subjected to chiral resolution using

NKR-chromatography using SpPiga!iRak AB-N (250 X 10 mm, particle size 5 μm) with a mobile phase of 2895 acetonitrile/methanol (90:10)/72 95 carbon dioxide (introduced volume - 500 μl of solution 32 mg/ml in acetonitrile/methanol (90:10)) with obtaining as the first eluted enantiomer (14p)-12,12-dimethyl-8-(3-73-11-

Zo (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23 ),5,7,9,19,21-hexane-2,2,4-trione (compound 190) (82.3 mg, 49 90). MO-IER t/: calc. 647.2502, found 648.1 (M.-1) same; retention time: 2.21 min. (Method of RH B).

Example 172: Preparation of (145)-8-(3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23- pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 193) o (i M ( Kd

D Eh M sh xx m? huh

M ttn se i. To vyvri x u ee nok sh MAKA S

Stage (1: (145)-8-I3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo !|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 193).

X is your FSheva? a - si M m M zh r | 2 to Iv

МН жк шаф

(145)-8-chloro-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(23) was introduced into the vial. 5,7,9,19,21-hexane-2,2,4-trione (60 mg,

0.1333 mmol), 1-(4,4-dimethylpentyl)imidazolidinyl-2-one (50 mg, 0.2713 mmol), cesium carbonate (155 mg, 0.4757 mmol), 4,5-bisidiphenylphosphino)-9 ,9-dimethylxanthene (12 mg, 0.02074 mmol) (xanthphos) and anhydrous dioxane (2.0 mL) in the indicated order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Rag(aba)z (12 mg, 0.01328 mmol) was then added under nitrogen and nitrogen was bubbled through the mixture for another 2 min, and then the vessel was capped under nitrogen. The mixture was stirred at 115 °C for 13 h. The mixture was allowed to cool to ambient temperature and then neutralized with glacial acetic acid (70 μL, 1.231 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through UMpaytap syringe disc filter with PTFE 0.45 μm The sample was purified by preparative reversed-phase HPLC-MS 130-99 95 acetonitrile in water (hydrochloric acid as a modifier).

Fractions of the desired product were combined and concentrated under reduced pressure and then dried under high vacuum to give (145)-8-13-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl -2A6b-thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2 ,4-trione (Compound 193) (29 mg, 3695) as a pale yellow solid. 1H NMR (400 MHz, Me VPapo!-a4) b 7.70 (a, 9 - 6.6 Hz, 1H), 7.52 (aa, 9 - 8.5, 7.2

Hu, 1H), 7.44 (a, U - 68.6 Hz, 1H), 7.15 (ad, 9 - 7.2 Hu, 1H), 6.65 (a, U - 8.5 Hu, 1H), 4.14 - 3.94 (t, ZN), 3.52 (aa, 9 - 9.8, 7.0, 3.2 Hz, 2H), 3.24 (ad, y - 7.2 Hz, ZH), 3.09 - 2.97 (t, 1H), 2.86 (y, U - 10.4 Gu, 1H), 2.23 - 2.08 (t, 1H), 1.83 (ai, U - 11.3, 5.1 Gu, 2H), 1.65 - 1.63 (t, ЗН), 1.63 - 1.55 (t, 4Н), 1.55 (5, ЗН), 1.42 (d , U 2 11.5 Hu, 1H), 1.29 (5, 1H), 1.26 - 1.19 (t, 2H), 0.92 (5, 9H). MO-IER t/ calc. 597.30975, found 598.5 (M--1)k; Holding time: 2.08 min. (Method of RH B).

Example 173: Preparation of 12,20,20-trimethyl-4(3-2-(1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa- 2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound 199)

M Go) m

IF) 5 2 yh ben O.O m-n -y m-m t DI RMV7 "XH "mV

РМВ "mV tyzhige oi hedioizgoteg5 tikhiige oi hedioivotege

MBO

(c) o oo m A M ri m o 7» Y 7 Y xx zivrya NA 5 as well as vkh zvrvondE: x sivrb - Ma M- i M-. and -e-Zhry " in rmy and iv "kv VosM tikhitsge oi hedioisotege tikhitsge oi hedioisotege

M o o,s o, 2 M o

Men ZHI on in KZ M and M | - va o em Mche mu ber uv Z na poshi: you and dad

Stage 1: 3-iodo-1-(4-methoxyphenyl)methyl|-4-methylpyrazole and 5-iodo-1-((4-methoxyphenyl)methyl|-4-methylpyrazole (mixture of regioisomers).

And ykh -O Y» | x --x

RM RM tihiige oi gedioivoteg5

M-iodosuccinimide (27.4 g, 121.79 mmol) was added to a solution of 4-methyl-1H-pyrazole (10 g, 121.80 mmol) in dimethylformamide (100 mL) at room temperature. The mixture was stirred overnight, then poured into water (700 mL) and extracted with ethyl acetate (4 x 150 mL).

The organic phases were combined and washed with water (3 x 150 ml) and brine (150 ml), dried with sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude iodinated intermediate compound. To a solution of crude iodinated material (2 g, 9.154 mmol) and potassium carbonate (2 g, 14.471 mmol) in acetonitrile (15 mL) was added 1-(chloromethyl)-4-methoxybenzene (1.5015 g, 1.3 mL, 9 .5876 mmol). The mixture was stirred at 80 C overnight before concentration under reduced pressure. The residue was suspended in dichloromethane (80 mL). After stirring for 10 minutes, the mixture was mixed with silica gel before concentration. The dry residue was introduced into a column with silica gel and eluted with 0-30 95 ethyl acetate in heptane to obtain 3-iodo-1-((4-methoxyphenyl)methyl|-4-methylpyrazole and 5-iodo-1-K(4-methoxyphenyl)methyl )|-4-methylpyrazole (mixture of regioisomers) (1.36 g, 43 95) as a pale yellow solid. MO-IER t/2 calc. 328.0073, found 329.0 (Ma-1); retention time: 2.02 min. (Method RH I).

Step 2: 2-Ethylhexyl-3-(11-(4-methoxyphenyl)methyl|-4-methylpyrazole-3-yl phenylsulfanylpropanoate and 2-ethylhexyl 3-(2-N4-methoxyphenyl)methyl|-4-methylpyrazole-3 - il|!isulfanylpropanoate (mixture of regioisomers) oo oo

X/ o y (9) 5 ! ! aa 2-4 aa | y schu y i shk o -y M o shk

Kh-m In DG gMv RMV

RM RMV tikhige oi hedioizotetg5 tikhiige oi hedioigotege

A solution of 3-iodo-1-(4-methoxyphenyl)methyl|-4-methylpyrazole and 5-iodo-1-(4-methoxyphenyl)methyl|-4-methylpyrazole (a mixture of regioisomers) (1.34 g, 4.0835 mmol) and diisopropylethylamine (1.05685 g, 1.44 mL, 8.2674 mmol) in toluene (25 mL) were degassed by bubbling nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium (0) (111 mg, 0.1212 mmol), xanthophos (142 mg, 0.2454 mmol) and 2-ethylhexyl-3-sulfanylpropanoate (986 mg, 4.5156 mmol) were added, the vial was sealed and the mixture was heated at 110 "C overnight.

The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 95 to 20 95 ethyl acetate in heptanes to give 2-ethylhexyl-3-(1-(4-methoxyphenyl)methyl|-4-methylpyrazol-3-yl|sulfanylpropanoate and 2-ethylhexyl -3-(2-(4-methoxyphenyl)methyl|-4-methylpyrazol-3-yl|sulfanylpropanoate (mixture of regioisomers) (1.54 g, 90 9o) in the form of orange oil. MO-IER t/: calc. 418,229 , found 419.3 (M.H1T) zhk, retention time: 2.58 min (Method RH I).

Stage 3: |1-(4-Methoxyphenyl)methyl)|-4-methylpyrazol-3-yl|sulfinyloxysodium and 12-(4-methoxyphenyl)methyl)|-4-methylpyrazol-3-yl|Isulfinyloxysodium (mixture of regioisomers)

Ku ya m o (in) o 5 o 5 Her HER le. Oh

Ks m Z tv z YN

RM RMV tihiige oi hedioivoteg5 tihiige oi hedioizoteg5

Sodium methoxide (750.17 mg, 13.886 mmol) was added to a solution of 2-ethylhexyl-3-(1-((4-methoxyphenyl)methyl)|-4-methylpyrazol-3-yl|!isulfonylpropanoate and 2-ethylhexyl-3- (2-(4-Methoxyphenyl)methyl)|-4-methylpyrazol-3-yl!isulfonylpropanoate (mixture of regioisomers) (1.56 g, 3.4621 mmol) in tetrahydrofuran (4 mL) and methanol (1.4 mL) at room temperature.

The reaction mixture was stirred for 2 hours, then the mixture was concentrated under reduced pressure to obtain I|1-(4-methoxyphenyl)methyl)|-4-methylpyrazol-3-yl|Isulfinyloxysodium and (2-

K4-methoxyphenyl)methyl)|-4-methylpyrazol-3-yl|sulfinyloxysodium (mixture of regioisomers) (1.04 g, 104 95) as a beige solid. MO-IER t/:2 calc. 288.0545, found 289.1 (M--T) zhk; retention time: 1.5 min. (Method RH I).

Stage 4: 1-C4-methoxyphenyl)methyl|-4-methylpyrazole-3-sulfonamide and 2-C4-methoxyphenyl)methyl)|-4-methylpyrazole-3-sulfonamide (mixture of regioisomers).

o o o o o da Y KT Mar ra Z ra to o More: ts nm in /Y Z | ---yaz"" And no

M x ut x

RM RMV RM RM tihichge oi hedioisoteg5 tihiyge oi hedioisoteg

Hydroxylamine-O-sulfonic acid (9.7 g, 85.770 mmol) was added to a solution of (|1-((4-methoxyphenyl)methyl)|-4-methylpyrazol-3-yl|sulfinyloxysodium and (|2-(4-methoxyphenyl) )methyl|i- 4-methylpyrazol-3-yl|Isulfinyloxysodium (mixture of regioisomers) (12.4 g, 43.011 mmol) and sodium acetate (10.5 g, 128.00 mmol) in water (400 mL) at 0 " C. The mixture was stirred at room temperature overnight and then extracted with ethyl acetate (2 x 300 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 20 95 to 60 95 ethyl acetate in heptanes. , to obtain 1-K4-methoxyphenyl)methyl|-4-methylpyrazole-3-sulfonamide and 2-(4-methoxyphenyl)methyl|-4-methylpyrazole-3-sulfonamide (mixture of regioisomers) (9.72 g, 8095) in in the form of an off-white solid. MO-IER t/72 calcd. 281.0834, found 282.1 (M--1)-k, retention time: 1.51 min (Method RH I).

Stage 5: 4-methyl-1H-pyrazole-3-sulfonamide o (c) (o) (c)

U ti Kk /,/ ra tiy t NOM | yh N m? in; that -- zhk 2 | Ex

M--k Mk M

RMV7 |: Shi

RM tihkihe oi hedioisoteg

A solution of 1-K4-methoxyphenyl)methyl|-4-methylpyrazole-3-sulfonamide and 2-(4-methoxyphenyl)methyl)|-4-methylpyrazole-3-sulfonamide (mixture of regioisomers) (270 mg, 0.9597 mmol) in trifluoroacetic acid (2 ml) was stirred at 80 C overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 2095 to 100 96 ethyl acetate in heptanes, then isocratic 10 90 methanol in ethyl acetate to give 4-methyl-1H-pyrazole-3-sulfonamide (120 mg, 7895) as a white solid substance. 1H NMR (300 MHz, DMSOSO-ab6) mp 2.12 (5, 3H), 7.29 (v, 2H), 7.64 (5, 1H), 13.11 (Brg. 5., 1H). MO-IER t/ calc. 161.0259, found 162.1 (M.-1) k; Holding time: 0.46 min. (Method RH I).

Stage 6: tert-butyl 2,2-dimethyl-4-(3-(4-methyl-3-sulfamoyl-pyrazol-1-yl)/propyl|pyrrolidine-1-carboxylate o o

M

5

MBO tiy x vh o o o M-M

M

5 years nm! entrance and m-n

VosmM

VosmM

Solution // tert-butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (750 mg, 2.236 mmol), potassium carbonate (772 mg, 5.586 mmol) and 4-methyl-1H-pyrazole -3-sulfonamide (300 mg, 1.861 mmol) in N,M-dimethylformamide (3 mL) was stirred at 807 for 4 hours. The mixture was filtered and dissolved in diethyl ether. The mixture was washed

with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel (095 to 30905 ethyl acetate in hexane), which resulted in poor resolution. The mixed fractions were combined, evaporated and separated by preparative reversed-phase HPLC (C18, 1-99 95 acetonitrile in water/hydrochloric acid modifier) to obtain as the first eluted major regioisomer tert-butyl-2,2-dimethyl-4-( 3-(4-Methyl-3-sulfamoyl-pyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (200 mg, 27,965). NR NMR (400

MHz, Spiogotogyt-a) 6 7.23 - 7.19 (t, 1H), 5.06 (5, 2H), 4.08 (y, U - 7.0 Hz, 2H), 3.65 (aa, U - 10.2, 7.6

Gu, 1H), 2.82 (I, U - 10.6 Gu, 1H), 2.26 (a, U - 0.7 Hz, ZN), 2.11 - 1.97 (t, 1H), 1.92 - 1.82 (t, ZN), 1.66 - 1.58 (t, 1H), 1.46 (5, 9H), 1.39 (v, ЗН), 1.37 - 1.30 (t, 2Н), 1.27 (5, ЗН). MO-IER t/2 calc. 400.21442, found 401.26 (M--1); Holding time: 0.65 min. (Method of RH A).

Stage 7: 2-chloro-N-(1-3-(5,5-dimethylpyrrolidin-3-yl)propyl|-4-methyl-pyrazol-3-yl|sulfonyl-6-13-(2-P1-( trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (hydrogen chloride salt) y y o y | Match -- 5-7 MU s shk eco i her

VosM nu

From a 50 mL flask charged with carbonyldiimidazole (73 mg, 0.4502 mmol) and 2-chloro-6-I3-(2-

N-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (170 mg, 0.4525 mmol) was pumped off with nitrogen, then backfilled with nitrogen. Tetrahydrofuran (5 mL) was added, and the mixture was stirred at 50 "C for 1 hour. Then, tert-butyl-2,2-dimethyl-4-(3-(4-methyl-3-sulfamoylpyrazol-1-yl)propyl) solution was added |pyrrolidine-1-carboxylate (150 mg, 0.3745 mmol) and 1,8-diazabicyclo(|5.4.F)undec-7-ene (143 mg, 0.9393 mmol) in tetrahydrofuran (4 mL) and the mixture was stirred overnight at 50 "C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated and purified by preparative reversed-phase HPLC (C18, 1 9595-9995 acetonitrile in water/hydrochloric acid modifier) to give the intermediate acylsulfonamide , which was dissolved in dioxane (5 mL), treated with hydrochloric acid (1.3 mL of 6 M in dioxane, 7.800 mmol) and stirred at room temperature for 3 h. -(5,5-dimethylpyrrolidin-3-yl)/propyl|-4-methylpyrazol-3-yl|sulfonyl-6-

13-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (hydrochloride salt) (57 mg, 22 95). MSO-IER ip/2 calc. 657.2112, found 658.32 (M'-1) k; retention time: 0.6 min. (Method of RH A).

Stage 8: 12,20,20-trimethyl-4-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9 ...

M

WITH

KT va 0 Mi Mk

NS with CHI -sh- nyu

5 ml of 2-chloro-M-(1-(3-(5,5-dimethylpyrrolidin-3-yl)/propyl|)-4-methylpyrazol-3-yl|sulfonyl-6-I(3- (2-I11-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridin-

Z-carboxamide (hydrochloride salt) (57 mg, 0.08206 mmol), potassium carbonate (58 mg, 0.4197 mmol), cesium fluoride (25 mg, 0.1646 mmol) and molecular sieves Z A (300 mg), and purged with nitrogen.

Dimethyl sulfoxide (3 mL) was added and the mixture was stirred at 150 °C overnight. The mixture was filtered and purified by preparative reversed-phase HPLC (C18, 1 95-99 95 acetonitrile in water/hydrochloric acid modifier) to give 12,20,20-trimethyl -4-(3-12-|(1- (trifluoromethyl)cyclopropyl|ethoxy)-1 H-pyrazol-1-yl)-10A6-thia-1,3,9,14 22- pentaazatetracyclo|16.2.1.111,14.02 ,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (Compound

199) (6.2 mg, 12 95). MSO-IER t/2 calc. 621.2345, found 622.35 (M-1)k; retention time: 2.16 min. (Method of RH B).

Example 174: Preparation of (145)-8-(3-cyclohexyl-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo|1 7.3.1.111 ,14.05,10|tetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 200) p KUYA OO oo o) V c M

SA dO a rr i / Y si My she 4 p SU M pav she

Master of cabinetry

Stage 1: (145)-8-(33-Cyclohexyl-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 200). about Y M I M

D y: M 5 o eh m z

OK. OO Olya

U / x si M M -0-- m M m M chief zdo:

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione (50 mg, 0.1075 mmol), 1-cyclohexylimidazolidin-2-one (26 mg, 0.1545 mmol) , Rag(ara)3 (26 mg, 0.02839 mmol), xanthophos (16 mg, 0.02765 mmol), cesium carbonate (180 mg, 0.5525 mmol), and anhydrous dioxane (800 μL). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120 °C for 20 h, and then cooled to room temperature.

The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by reversed-phase preparative chromatography using a C18 column (10 95-99 96 acetonitrile in water - 5 mM hydrochloric acid).

The product fractions were combined, saline solution was added and organic solvents were evaporated.

The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered, and evaporation of the solvents gave a solid. The product was further purified by chromatography on silica gel using a gradient from 100 95 dichloromethane to 595 methanol in dichloromethane to give (145)-8-(3-cyclohexyl-2-oxoimidazolidin-1-yl)-12,12 -dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexaene -2,2,4-trione (compound 200) (22.5 mg, 36 90). IN NMR (400 MHz, Spiogoitogt-a) 6 10.79 (5, 1H), 8.01 (y, U - 8.7 Hz, 1H), 7.90 (y, U - 8.8 Gu, 1H), 7.55 (d, U 5 2.9, 2.1 Hz, 2H), 6.54 (ai, U - 5.4, 3.7 Hz, 1H), 4.80 (5, 1H), 3.99 (ad, U - 9.1, 7.1 Hz, 2H), 3.83 (5, 2H), 3.45 ( I, 7 - 8.1 Hz, 2H), 3.32 (I, 9 - 68.9 Hz, 1H), 3.23 - 3.10

Zo (t, 1H), 3.04 (i, U - 9.4 Hu, 1H), 2.71 (5, 1H), 2.12 (ai, U - 12.4, 8.6 Hu, 1H), 1.84 - 1.76 (t, 4H), 1.69 (a, 9 - 13.2 Gu, 2H), 1.56 (a, U - 5.2 Hz, 8H), 1.43 - 1.36 (t, 4H), 1.15 - 1.06 (t, 1H), 0.91 - 0.85 (t, 1). MO-IER t/2 calc. 581.27844, found 582.2 (Ma1)-; retention time: 1.86 min. (Method of RH E).

Example 175: Preparation of / 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo |16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12- pentane-8,10,10-trione (enantiomer 1) (Compound 201) and 4-I3-( 3,33-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl-10X6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa -2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 202)

m o o, o M i, BI Me vvshOTU M si schi NU

OM (Y M Y M

BVKshO ry I She does

Stage 1: 2-Chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-H1-(3-(5,5-dimethylpyrrolidin-3-yl)/upropyl|-4-methyl -pyrazol-3-yl|isulfonylpyridine-3-carboxamide (hydrochloride salt)

M o o o

ON i them r r mem 5 on | with H M Z as m | ru 07 sa si th-k 7 M si . - J

VosM

NM

From a 50 mL flask charged with carbonyldiimidazole (78 mg, 0.4810 mmol) and 2-chloro-6-|3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (174 mg, 0.4809 mmol) was pumped out with nitrogen and refilled with it. Tetrahydrofuran (8 ml) was added and the mixture was stirred at 50 "C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-

IZ-(4-methyl-3-sulfamoylpyrazol-1-yl)propyl|pyrrolidine-1-carboxylate (160 mg, 0.3995 mmol) and 1,68-diazabicyclo|5.4.Fundec-7-ene (160 mg, 1.051 mmol) in tetrahydrofuran (4 ml) and the mixture was stirred overnight at 50 °C. The reaction was diluted with ethyl acetate and washed with water.

The organic phase was dried over sodium sulfate, evaporated and purified by chromatography on silica gel (from 095 to 50 95 ethyl acetate in hexane) to obtain some pure fractions.

The mixed fractions were re-purified by reversed-phase preparative HPLC (C18, 1 95-99 95 acetonitrile in water/hydrochloric acid modifier), and the pure material obtained was combined with the pure fractions from the original column with silica gel to obtain the intermediate acylsulfonamide. A solution of the intermediate acylsulfonamide in dioxane (5 mL) was treated with hydrochloric acid (1.3 mL, 6 M in dioxane, 7.800 mmol) and stirred at room temperature for 3 hours. The mixture was concentrated by evaporation to give 2-chloro-6-I|3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-N-(1-I3-(5,5-dimethylpyrrolidin-3-yl)propyl| -4- methylpyrazol-3-yl|!isulfonylpyridine-3-carboxamide (hydrochloride salt) (160 mg, 59 95). MO-

IER t/2 calc. 643.27075, found 644.38 (M.-1) k; retention time: 0.65 min. (Method of RH A).

Stage 2: 4-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl-10Abthia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111, 14.02,7 | docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione

PO about their mm

SHY -8 o um My m | 7 and | With weight 5-07 M M shk no - no

5 ml of 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-

M-P1-(3-(5,5-dimethylpyrrolidin-3-yl)ipropyl|-4-methylpyrazol-3-yl|sulfonylpyridine-3-carboxamide (hydrochloride salt) (160 mg, 0.2351 mmol), potassium carbonate (165 mg, 1.194 mmol), cesium fluoride (73 mg, 0.4806 mmol) and molecular sieves Z A (300 mg) and purged with nitrogen. Dimethyl sulfoxide (4 mL) was added and the mixture was stirred at 150 °C overnight. The mixture was filtered and purified by reverse-phase preparative HPLC (C18, 1 9595-9995 acetonitrile in water/hydrochloric acid modifier) to obtain 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20, 20-trimethyl-10X6-thia-1,3,9,14,22- pentaazatetracyclo/16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8, 10,10-trione (53.7 mg, 38 95). MSO-IER t/2 calcd 607.29407, found 608.41 (M--1)k; retention time: 2.36 min (Method

RK B).

Stage 3: 00 4-III-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl-10X6-thia-1,3,9,14,22-pentaazatetracyclo| 16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 201) and 4-I3-(3 ,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl-10A6-thia-1,3,9,14,22-pentaazatetracyclo|16.2.1.111,14.02,7|docosa- 2(7),3,5,11(22),12- pentane-8,10,10-trione (enantiomer 2) (Compound 202) shk I and OM 4-III-(3,3-dicyclopropylpropoxy)- 1 H-pyrazol-1-yl|-12,20,20-trimethyl-10A6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7| docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (53.7 mg) was subjected to chiral separation using NCR chromatography using SpigaIRak

AB-3 (150 x 2.1 mm, particle size 3 μm) with a mobile phase of 32 95 acetonitrile/methanol (90:10)/68 9o carbon dioxide at 0.5 ml/min for 6.0 min (1.6 mg/ml solution in acetonitrile/methanol (90:10)) with obtaining as the first eluted enantiomer 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl -10X6-thia-1,3,9,14,22- pentaazatetracyclo|16.2.1.111,14.02,7|docosa-2(7),3,5,11(22),12-pentane-8,10,10 -trione (enantiomer 1) (Compound 201) (3.5 mg, 5 95). MO-IER t/72 calc. 607.29407, found 608.38 (Ma1)xk; retention time: 2.36 min. (Method of RH B). The second eluted enantiomer was 4-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,20,20-trimethyl-10X6-thia-1,3,9,14,22- pentaazatetracyclo/ 16.2.1.111,14.02,7|docose-2(7),3,5,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 202) (5.0 mg, 7 90). MO-IER t/2 calc. 607.29407, found 608.3 (MA) k; Holding time: 2.49 min. (Method of RH B).

Example 176: Preparation of 8-13-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo! 17.3.1.111,14.05,10|)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 203) and 00 8-13-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl1-12,12,18-trimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloyl17.3.1. 111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 204)

THE HOUSE IS STILL IN O. em 4 M o to o. en M M Sho - o lk ky M z

BK koe BVKshch-UYA ko: -NVKUYA lk spapiyuteg! spapiotega

Stage 1: 8-III-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!| 17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 203) and 8-I3- (3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|- 12,12,18-trimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10 )hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 204)

DOM still Y U nd a and a de eta Sho: « p still

VK koe VK ko: BVKIOl'A Zh

Racemic 8-(3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!| 17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (76 mg) by chiral NCR chromatography. The following protocol was used

NKRKH: SpigaIiRak AZ-N (250 X 10 mm), 5 μm; mobile phase: 38 95 acetonitrile:methanol (90:10), b2 o carbon dioxide, injection of 70 μl of a solution of 16 mg/ml in a mixture of acetonitrile:methanol:dimethylsulfoxide (74:8:18) at a speed of 10 ml/min. The first eluted enantiomer was 8-13-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (compound 203) (3.5 mg, 6 95) in the form of a white solid. MO-IER t/72 calc. 633.30975, found 634.4 (Ma-1)k; retention time: 1.54 min. (The RH method.)). The second eluted enantiomer was 8-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-12,12,18-trimethyl-2.Ab-thia-3,9,11,18,23-pentaazatetracycloi |17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (compound 204) (3,5 mg, 6 95) in the form of a white solid. MO-IER t/2 calc. 633.30975, found 634.4 (Ma-1)-; retention time: 1.54 min. (The method of RH U).

Example 177: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(13-11-(trifluoromethyl)cyclopropyl|propyl)imidazolidinyl-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 205 ) (0)

Kt Ver 1 Kk NM MVos ererg with MVos Zierz (in) O oo

D M her se nn V v a fr y SI 4 M Me r ME m M 2

M

MN Kt or cabinets

Stage 1: 3-P1-(trifluoromethyl)cyclopropyl|Ipropanal o on H all with all

Dess-Martin periodate (880 mg, 2.075 mmol) was added to a stirred solution of 3-(1-(trifluoromethyl)cyclopropyl|Ipropan-1-ol (350 mg, 1.665 mmol) in anhydrous methylene chloride (10 mL) at 0°C (bath with ice) under a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature (and stirring was continued for another 3 hours. The reaction mixture was diluted with ether (60 mL) and saturated aqueous sodium bicarbonate (20 mL) was slowly added (to reducing the evolution of carbon dioxide gas). Sodium thiosulfate (10 mL) was then added and the mixture was stirred at ambient temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with ether (2 x 20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (rotary evaporator, pressure 300 mbar, so that some volatile products did not evaporate) to obtain 3-/1-(trifluoromethyl)cyclopropyl|Ipr opanal (250 mg, 90 95) in the form of a yellow oil. This material was used in the next reaction without

From drying to clean material and without additional cleaning. TN NMR (400 MHz, Veplepe-ab) b 9.15 (5, 1H), 1.99 - 1.90 (t, 2H), 1.52 - 1.44 (t, 2H), 0.68 - 0.59 (t, 2H), 0.00 (ai, 9 - 2.5, 1.6 Gu, 2H).

Stage 2: tert-butyl M-(2-IZ3-P1-trifluoromethyl)cyclopropyl|propylamino|ethyl|carbamate (o;

N nm Mvos MN Mvos gzo x ? X / --- z» o) M /

To the mixed solution tert-butyl. M-(2-aminoethyl/ucarbamate (242 mg, 1.510 mmol) in anhydrous methanol (7 mL) was added to a solution of 3-(/1-(trifluoromethyl)cyclopropyl|Ipropanal (250 mg, 1.505 mmol) in anhydrous methanol (1 mL) under a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 h, it was cooled to 0 °C (ice bath). Sodium borohydride (125 mg, 3.304 mmol) was then slowly added in two portions, and the mixture was allowed to warm to ambient temperature medium and stirring was continued for 13 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 15 mL) and brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product tert-butyl M-(2-IZ-1-(trifluoromethyl)cyclopropyl|Ipropylamino|ethylI|Icarbamate (467 mg, 10095) as a yellow oil contaminated with some bis-adduct. This matter l was transferred directly to the next stage. MO-IER tp/2 calc. 310.1868, found 311.3 (M--1)k; retention time: 1.17 min. (Method of RH B).

Stage 3: 1-3-1-trifluoromethyl)cyclopropyl|propylimidazolidinyl-2-one (c)

MN MVos D go M / - 5 3 M MN vs XM y

Solid potassium tert-butoxide (275 mg, 2.451 mmol) was added to a solution of crude tert-butyl-M-(2-(3-P1-(trifluoromethyl)cyclopropyl|Ipropylamino|ethylcarbamate) (250 mg, 0.8055 mmol, contaminated with some bis -adducts from the previous stage) in anhydrous tetrahydrofuran (10 ml) in a nitrogen atmosphere and the reaction mixture was heated to 70 "C for 13 h. The reaction mixture was allowed to cool to ambient temperature and the reaction mixture was acidified to pH 4-5 with aqueous hydrochloric acid (2 .5 mL of 1 M, 2.500 mmol.) After removal of volatiles under reduced pressure, the aqueous residue was extracted with ethyl acetate (3 x 25 mL).

The combined organic layers were washed with saline (2 x 20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 90-10 90 methanol in a methylene chloride gradient) to obtain 1-

13-[1-(trifluoromethyl)cyclopropyl|propylimidazolidinyl-2-one (72 mg, 38 90) as an off-white solid. 1H NMR (400 MHz, Veplepe-ab) b 5.35 (5, 1H), 2.84 (I, U - 6.8 Hz, 2H), 2.54 - 2.41 (t, 4H), 1.33 - 1.25 (t, 2H), 1.23 - 1.17 (t, 2H), 0.63 - 0.54 (t, 2H), 0.05 - -0.06 (t, 2H). MO-

IER t/2 calc. 236.11365, found 237.1 (M--1) k; retention time: 0.93 min. (Method of RH B).

Stage 4: (145)-12,12-dimethyl-8-(2-oxo-3-(3-11-(trifluoromethyl)cyclopropyl|propyl)imidazolidinyl-1-yl)-2A6-thia-3,9,11 ,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 205) (c) o o o

Zhd r zh o 5 and s. S. I. M. Ma

Kk s M M i X, M M -n-ya y) s CHIY uc MN

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione, (50 mg, 0.1111 mmol), 1-IZ3-/1-trifluoromethyl)cyclopropyl|propyl|imidazolidinyl -2-one (32 mg, 0.1355 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bis(idiphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) ( xanphos) and anhydrous dioxane (1.1 mL) in this sequence. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Then, nitrogen was added in the atmosphere

Rag(aura)z (10 mg, 0.01107 mmol) and nitrogen was bubbled through the reaction mixture for another 2 min and the reaction mixture was closed under a nitrogen atmosphere. The mixture was stirred at 115 °C for 14 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μL, 0.8792 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through syringe disc filter M/paytap with PTFE 0.45 μm The sample was purified by preparative reversed-phase HPLC-MS (30-99 95 acetonitrile in water (hydrochloric acid as a modifier)).

Fractions of the desired product were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25 ml) and washed successively with saturated aqueous sodium bicarbonate (2 x 10 ml) and saline (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (145)-12,12-dimethyl-8-(2-oxo-3-(3-/1-(trifluoromethyl)cyclopropyl|propyl)imidazolidine- 1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20- hexane-2,2,4-trione (compound 205) (19.0 mg, 26 95) as an off-white solid. 1H NMR (400

MGu, Meiipapoi-a4) b 7.70 (a, 9U - 8.5 Gu, 1H), 7.53 (aa, U - 8.5, 7.2 Hz, 1H), 7.43 (a, U - 8.6 Hz, 1H), 7.15 (aa, 9 - 7.2, 0.8 Hz, 1H), 6.65 (aa, U - 8.5, 0.8 Gu, 1H), 4.14 - 4.07 (t, 1H), 4.07 - 4.02 (t, 1H), 4.02 - 3.95 (t, 1H), 3.56 - 3.45 (t, 2H), 3.29 - 3.19 (t, ZH), 3.03 (y, U - 13.8 Hz, 1H), 2.86 (I, U - 10.4

Gu, 1H), 2.21 - 2.09 (t, 1H), 1.83 (aa, U 2 11.7, 5.4 Hz, 2H), 1.78 - 1.69 (t, 2H), 1.69 - 1.63 (t, 4H, rapshayu orzsigea Bu gezidtsa! mageg reak), 1.61 (a, 9 - 5.6 Hz, 2H), 1.60 - 1.57 (t, 1H), 1.55 (5, ЗН), 1.42 (d, 9U - 11.5 Hz, 1H), 1.32 - 1.26 (t, 1H), 0.96 - 0.90 (t, 2H), 0.72 - 0.66 (t, 2H). MO-IER t/27 calc. 649.2658, found 650.4 (M--1) k; retention time: 1.92 min. (Method of RH B).

Example 178: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-12-11-(trifluoromethyl)cyclopropyl|ethyl)imidazolidinyl-1-yl)-2A6-thia-3,9,11 ,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 211) Щ Bivr1 and nm MNVos Bier2 M and MNVos vierz

Kk z as I NM / - vv My drank (o) o ooo

X sh ri Eh Y MU

We are MN, | M | vyvr4 o | and M | y: all of us

SI M M Z it M m M ih we all or Mn

Stage 1: 2-P1-(trifluoromethyl)cyclopropyl|acetaldehyde (c) co: -- c

N

Dess-Martin periodate (2.43 g, 5.729 mmol) was added to a stirred solution of 2-(1-(trifluoromethyl)cyclopropyl|ethanol (700 mg, 4.542 mmol) in anhydrous methylene chloride (15 mL) at 0 "C (water bath with ice) under a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 3 hours. The reaction mixture was diluted with ether (60 mL) and saturated aqueous sodium bicarbonate (20 mL) was slowly added (to reduce the of carbon dioxide gas). Sodium thiosulfate (10 mL) was then added and the mixture was stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2 x 20 mL). The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (at 300 mbar to avoid evaporation of some volatile

From the products) to obtain 2-|1-(trifluoromethyl)cyclopropyl|acetaldehyde (500 mg, 72 Fo) in the form of crude material. Because of its volatility, it was not dried or cleaned. TTN NMR (400 MHz,

Vepgepe-ab) b 9.24 (H, U - 2.3, 1.2 Hz, 1H), 1.77 (y, U - 2.4 Hz, 2H), 0.66 - 0.59 (t, 2H), 0.00 (da, y - 4.4, 2.3 Hz , 2H). 19E NMR (376 MHz, benzene-ab) b -70.56.

Stage 2: tert-butyl M-(2-(2-P1-"trifluoromethyl)cyclopropyl|ethylamine|ethyl carbamate o M ie МНВос nm МНВос о ko? - n--

With Kk M / all M /

To the mixed solution tert-butyl. To a solution of M-(2-aminoethyl/ucarbamate (527 mg, 3.289 mmol) in anhydrous methanol (15 mL) was added a solution of 2-(/1-(trifluoromethyl)cyclopropyl|acetaldehyde (500 mg, 3.287 mmol) in anhydrous methanol (1 mL) under a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 h, it was cooled to 0 °C (ice bath). Sodium borohydride (260 mg, 6.872 mmol) was then slowly added in two portions, and the mixture was allowed to warm to ambient temperature medium and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 15 mL) and brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl M-(2-(2-11- (trifluoromethyl)cyclopropyl|ethylaminoethyl|Icarbamate) (970 mg, 10095) in the form of a yellow oil.

The crude material was used in the next step without any additional purification. MO-IER t/72 calc. 296.17117, found 297.3 (Ma-1)f; retention time: 0.79 min. (Method of RH B).

Stage 3: 1--2-1-"trifluoromethyl)cyclopropyl|ethylimidazolidinyl-2-one (c)

We MNVos X x / -VU- M MN o We x / what.

Solid potassium tert-butoxide (460 mg, 4.099 mmol) was added to a solution of tert-butyl-M-(2-(2-

P-(trifluoromethyl)cyclopropyl|ethylamine|ethyl|carbamate (400 mg, 1.350 mmol) in anhydrous tetrahydrofuran (20 ml) and the heterogeneous reaction mixture was heated at 70 "C for 13 hours.

The reaction mixture was allowed to cool to ambient temperature and acidified with glacial acetic acid (250 μL, 4.396 mmol). Volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel (0905-1095 methanol in methylene chloride gradient) to give 1-(2-(/1-«"trifluoromethyl)cyclopropyl|ethylimidazolidinyl-2-one (127 mg, 42 95) as an off-white solid. 1H NMR (400 MHz, Veplepe-ab) b 4.99 (5, 1H), 3.35 - 3.20 (t, 2H), 2.71 - 2.56 (t, 4H), 1.70 - 1.59 (t, 2H), 0.86 - 0.73 (t, 2H), 0.46 - 0.33 (t, 2H). MO-IER n/2 calc. 222.09799, found 223.1 (M--1)xh; retention time: 0, 78 min (Method

RK B).

Stage 4: (145)-12,12-dimethyl-8-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethyl)imidazolidinyl-1-yl)-2A6-thia-3,9, 11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 211 ) about z

From and to | y Я - -- Her y | with and KM ach A How ach

M

MN ke cho shaf

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14.05,10)hetracose- 1 (23), 5,7,9,19,21-hexane-2,2,4-trione (50 mg, 0.1111 mmol), 1-(2-P1-trifluoromethyl)cyclopropylethylimidazolidinyl-2- on (30 mg, 0.1350

zo mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bis(idiphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) (xanphos), and anhydrous dioxane (1 mL) in this sequence. Nitrogen was blown through the heterogeneous mixture for 2 min. Rag(aura)z (10 mg, 0.01107 mmol) was then added under nitrogen and the mixture was purged with nitrogen for another 2 minutes, then capped under nitrogen. The mixture was stirred at 115 °C for 14 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μL, 0.8792 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through syringe disk filter

UMpaytap with PTFE 0.45 μm. The sample was purified using reverse-phase preparative

HPLC-MS (30-99 95 acetonitrile in water (hydrochloric acid as modifier). Fractions of the desired product were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 mL) and washed with brine (10 mL). Organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellowish solid. -(2-oxo-3-(2-P1-trifluoromethyl)cyclopropyl|ethylimidazolidinyl-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracycloyl17.3.1.111,14.05,10 |hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 211) (18 mg, 2595) as an off-white solid. TN NMR (400 MHz,

Meipapo!-а4) b 7.71 (а, у - 8.6 Hz, 1Н), 7.52 (da, У - 8.5, 7.2 Hz, 1Н), 7.42 (y, У - 8.6 Гу, 1Н), 7.15 (99, У - 7.3, 0.8 Hu, 1H), 6.65 (a, U - 8.5 Hz, 1H), 4.17 - 4.03 (t, 2H), 3.99 (19, U - 10.2, 9.7, 6.7 Hz, 1H), 3.53 (aa, 9 - 9.5, 6.9, 2.5 Hz, 2H), 3.45 - 3.37 (t, 2H), 3.24 (I, U - 8.7 Gu, 1H), 3.03 (a, y - 13.7

Hu, 1H), 2.87 (I, U -10.5 Hu, 1H), 2.20 - 2.09 (t, 1H), 1.89 - 1.80 (t, 4H), 1.63 (5, ZN), 1.5941.9 - 12.2 Hu, 1H ), 1.54 (5, ZH), 1.48 - 1.38 (t, 1H), 1.29 (v5, 2H), 1.02 - 0.96 (t, 2H), 0.81 - 0.75 (t, 2H).

MO-ER t/2 calc. 635.2502, found 636.4 (M--1)k; retention time: 1.85 min. (Method of RH B).

Example 179: Preparation of (145)-8-13-(4,4-difluorocyclohexyl)methyl|-2-oxoimidazolidin-1-yl).12,12-dimethyl-2A6-thia-3,9,11,18,23 -pentaazatetracyclo!y17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 214) (o) n MN MNVos

NM MNVos Zier1 Mch Vier2

M / - --

E E

E E o o o o o

Heh uh and Moscow, | N | Vision From them y -Y | with

ХУ / ra M -Z5-zhke and si M M X, - m M i

E chn hi yin

IS

IS

Stage 1: tert-butyl M-(2-(4,4-difluorocyclohexyl)methylamino|ethylcarbamate o

Н МН МНВос

NM MNVos M

X / --I

E E

E E

To the stirred solution tert-butyl. To M-(2-aminoethyl)ucarbamate (325 mg, 2.029 mmol) in anhydrous methanol (15 mL) was added a solution of 4,4-difluorocyclohexanecarbaldehyde (300 mg, 2.025 mmol) in anhydrous methanol (1 mL) under a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 h, it was cooled to 0 °C (ice bath). Sodium borohydride (165 mg, 4.361 mmol) was then slowly added in two portions, the mixture was allowed to warm to ambient temperature, and stirring was continued. for 15 h. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2 x 15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl-M-(2-K4,4-difluorocyclohexyl)methylamino|ethyl|Icarbamate (590 mg, 10095) in the form of a yellow oil.

The crude material was used in the next step without any additional purification. 1H NMR (400 MHz, Vepgepe-ab) b 4.76 (5, 1H), 3.16 (d, U - 5.8 Hz, 2H), 2.35, 9 - 5.9

Gu, 2H), 2.05 (a, U - 6.5 Hz, 2H), 2.03 - 1.97 (t, 1H), 1.59 (5, 9H), 1.54 - 1.42 (t, 4H), 1.16 - 1.03 (t, 2H) , 1.02 - 0.84 (t, 1H), 0.48 (5, 2H). MO-IER t/: calc. 292.19623, found 293.3 (M.-1)k; retention time: 0.73 min. (Method of RH B).

Stage 2: 1-(4,4-difluorocyclohexyl)methylimidazolidinyl-2-one (c)

MN MNVos XX

M / M MN -i KhM u

IS

E E

IS

Solid potassium tert-butoxide (866 mg, 7.718 mmol) was added to the stirred solution of tert-butyl. M-(2-(4,4-difluorocyclohexyl)methylamino|ethylcarbamate (750 mg, 2.565 mmol) in

of tetrahydrofuran (12 ml), and the heterogeneous reaction mixture was heated at 70 "C for 13 hours.

After cooling to room temperature, the reaction mixture was acidified with glacial acetic acid (500 μL, 8.792 mmol) and concentrated under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate (15 mL) and ethyl acetate (25 mL), and the layers were separated. The aqueous portion was further extracted with ethyl acetate (25 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-K4,4-difluorocyclohexyl)methylimidazolidinyl-2-one (379 mg, 68 95). as an off-white solid. IN NMR (400 MHz, MeiPpapo!-a«) b 3.51 - 3.44 (t, 2H), 3.42 - 3.35 (t, 2H), 3.04 (y, - 7.1 Hu, 2H), 2.09 - 1.98 (t, 2H) , 1.83 - 1.65 (t, 5Н), 1.33 - 1.20 (t, 2Н). MO-IER t/: calc. 218.12306, found 219.1 (M.-1)xzh; retention time: 0.7 min. (Method of RH B).

Stage 3: (145)-8-13-(4,4-difluorocyclohexyl)methyl|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 214) o o o

Х Ех Ж s І M

M Mn, | And | about | xx M xx

Hu si M M M ikh -06- r 2 m M i

IS

/ ry apri

IS

IS

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose- 1(23),5,7,9,19,21-hexane-2,2,4-trione, (50 mg, 0.1111 mmol), 1-K4,4-difluorocyclohexyl)methylimidazolidinyl-2-one (34 mg, 0.1558 mmol),

Rag(aba)z (15 mg, 0.01638 mmol), xanthophos (16 mg, 0.02765 mmol), cesium carbonate (213 mg, 0.6537 mmol), and anhydrous dioxane (0.75 mL). The mixture was purged with nitrogen for about 5 minutes, closed with a lid and stirred at 120 "C for 22 hours. The reaction mixture was concentrated by blowing nitrogen into a vial. The reaction mixture was diluted with dimethyl sulfoxide (1.5 ml), microfiltered and subjected to reversed-phase preparative HPLC (С18) using a gradient of acetonitrile in water (from 1 9o to 99 Fo) and hydrochloric acid as a modifier. The pure fractions were collected and the organic solvents were evaporated. The solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate, then filtered.

Evaporation of the filtrate gave a solid which was purified by flash chromatography on silica gel using a gradient of methanol (0 95 to 5 95) in dichloromethane. The pure fractions were collected and the solvents were evaporated. The residue was triturated with dichloromethane/hexane and the solvents were evaporated to give (145)-8-13-((4,4-difluorocyclohexyl)methyl|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6-thia-3 ,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10)|hetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( compound 214) (20 mg, 27 95) as an off-white solid. IN NMR (400 MHz, DMSOO-ab) b 12.26 (5, 1H), 7.65 - 7.51 (t, 2H), 7.40 (0.9 -

Zo 8.6 Hz, 1H), 7.03 (a, 9U - 7.1 Hz, 1H), 6.94 (rhoad a, U - 9.1 Hu, 1H), 6.69 (y, U - 8.5 Hu, 1H), 4.03 - 3.85 (t, ЗН), 3.56 - 3.40 (t, 2Н), 3.18 - 3.03 (t, ЗН), 2.94 (y, U - 13.3 Hu, 1Н), 2.71 (a, U - 10.9 Hu, 1Н), 2.12 - 1.96 (t , ZN), 1.86 - 1.69 (t, 7H), 1.63 - 1.43 (t, 9H), 1.36 - 1.27 (t, 1H), 1.23 - 1.10 (t, 2H). MO-IER t/: calc. 631.2752, found 632.3 (M--1)f; retention time: 1.79 min. (The method of RH

IN).

Example 180: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidinyl-1-yl|-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 225) (c)

We are Zier 1 yr yr nm MNVos Ver? KO M/o o vyvrz vs --jo vs y, CHI - same M / ---k o oo

X XX Tk

KI | with Y | TZ faith o u y - M i -0b0y-k

SI M M sh X, ME m M i y y kohi MN

Stage 1: 3,3,3-trifluoro-2,2-dimethylpropanal and

Come on, N

Dess-Martin periodate (in dichloromethane) (5.4 g, 12.73 mmol) was added to a stirred solution of 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (2.0 g 75 95 wt ., 10.55 mmol) in anhydrous dichloromethane (30 ml) at 0 "С (ice bath) in a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (80 mL) and saturated aqueous sodium bicarbonate (30 mL) was slowly added (to reduce the evolution of carbon dioxide gas). Then a 10 95 solution of sodium thiosulfate (10 mL) was added and the mixture was stirred at ambient temperature for 30 minutes, during which time, all solids dissolved. The layers were separated and the aqueous layer was extracted with ether (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and partially concentrated under reduced pressure to about 3- 5 ml with obtaining 3,3,3-tr ifluoro-2,2-dimethylpropanal (1.37 g, 93 95) in the form of a crude solution in ether, which was used directly in the next stage. MSO-IER t/2 calc. 140.0449, found 141.2 (Ma-1) k; Holding time: 0.42 min. (Method of RH E).

Stage 2: tert-butyl M-(2-((3,3,3-trifluoro-2,2-dimethyl-propyl)amino|ethyl Icarbamate)

Iv) r nm MNVoOs KO /NVos es m /

Z H -- yuhn-z"

A crude ether solution of 3,3,3-trifluoro-2,2-dimethylpropanal (1.37 g, 9.778 mmol), described in the previous stage, in anhydrous methanol (8 mL) under a nitrogen atmosphere. After stirring the pale yellow solution at ambient temperature for 1 h, it was cooled to 0 "C (ice-water bath). Sodium borohydride (875 mg, 23.13 mmol) was slowly added in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 24 h. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 ml) and saline solution (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl M-(2-(3,3,3-trifluoro-2,2-dimethyl- propyl)amino|ethylcarbamate (777 mg, 36 95) in the form of pro star viscous oil. MO-IER t/2

From calculations 284.17117, found 285.2 (M--1)x; Holding time: 0.97 min. (Method of RH E).

Stage 3: 1-(3,3,3-trifluoro-2,2-dimethyl-propyl)imidazolidinyl-2-one (c) all МН МНВос ХХ

KO M / - z» me MN

Solid potassium tert-butoxide (860 mg, 7.664 mmol) was added to a solution of tert-butyl-M-(2-

I(3,3,3-trifluoro-2,2-dimethyl-propyl)amino|ethyl carbamate (777 mg, 2.733 mmol) in anhydrous tetrahydrofuran (40 mL), and the heterogeneous reaction mixture was heated at 70 "C for 18 hours.

The reaction mixture was allowed to cool to ambient temperature and acidified to pH -5 with aqueous hydrochloric acid (1 M). Volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saline (2 x 40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 90-10 906 methanol in methylene chloride) to obtain 1-(3,3,3-trifluoro-2,2-dimethylpropyl) imidazolidinyl-2-one (19.38 mg, C 95) in in the form of an off-white solid. 1N

NMR (400 MHz, Spiogoiopt-a) b 3.57 - 3.48 (t, 2H), 3.44 - 3.39 (t, 2H), 3.25 (y, 9U - 2.5 Hz, 2H), 1.16 (a, U - 5.9 Hz, 6H ). MO-IER t/: calc. 210.09799, 211.1 (Ma-1) found; Holding time: 0.94 min. (Method of RH E).

Stage 4: (145)-12,12-dimethyl-8-(2-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidinyl-1-yl|-2A6-thia-3, 9,11,18,23-pentaazatetracyclo|1 7.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( Compound 225) o n Kui o o o

X Z I zha y - your VO a rt x / si M M Sh-s r M M M ih

M

MN KO hi shaf!

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1( 23),5,7,9,19,21-hexane-2,2,4-trione (40 mg, 0.08890 mmol), 1-(3,3,3-trifluoro-2,2-dimethylpropyl) imidazolidinyl -2-one (20.56 mg, 0.09781 mmol), Rag(aura)z (21.5 mg, 0.02348 mmol), xanthophos (13.5 mg, 0.02333 mmol), cesium carbonate (150 mg, 0.4604 mmol) and anhydrous dioxane (800 μL). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120 "С for 20 h, and then cooled to room temperature. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by reversed-phase preparative chromatography using column C18 (10-99 90 acetonitrile in water with 5 mM hydrochloric acid for a run of 15 minutes). The product fractions were combined, brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, and evaporation of the solvents gave a solid . The solid was purified by chromatography on silica gel using a gradient of 100 95 dichloromethane to 5 956 methanol in dichloromethane. The pure fractions were collected, the solvents were evaporated, but impurities remained. The material was diluted with dimethyl sulfoxide (900 μl) and purified by reversed-phase preparative chromatography using a C18 column (20 95-80 96 acetonitrile in water - 5 mM hydrochloric acid for 30 minutes) to obtain an off-white solid (145)-12,12-dimethyl-8-(2-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl) imidazolidinyl-1-yl|-2A6b-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23) ,20-hexane-2,2,4-trione (compound 225) (1.9 mg, C 90). MO-IER t/2 calc. 623.2502, found 624.2 (Ma1)k; Holding time: 1.88 min. (Method of RH E).

Example 181: Preparation of (145)-8-(3-Cadamantan-1-yl)methyl)-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6b-thia-3,9,11,18,23 -pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 229) n o o o o

D J (m m/n | 7 Y | 75 vyvrz o xx M y

Hu t - M - y | N a m M M M M - still ry

Coo)

Stage 1: tert-butyl M-(2-(1-adamantylmethylamino)ethylcarbamate

Mn, oh MnVos I'm in --

N

To the mixed solution tert-butyl. M-(2-oxoethyl)ucarbamate (494 mg, 3.103 mmol) in anhydrous methylene chloride (20 mL) was added to a solution of 1-adamantylmethanamine (509 mg, 3.080 mmol) in anhydrous methylene chloride (1 mL), followed by the addition of glacial acetic acid (200 μL , 3.517 mmol) at ambient temperature in a nitrogen atmosphere.

The clear reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (1.0 g, 4.718 mmol) was added in one portion at ambient temperature and stirring was continued for 13 hours. Volatile substances were removed under reduced pressure. The residue was placed in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl-M-( 2-(1-Adamantylamino)ethylcarbamate (901 mg, 95 95) in the form of a yellow resinous substance. The crude substance was used in the next step without additional purification. MO-IER t/72 calc. 308.24637, found 309.4 (Ma1) - Retention time: 1.09 min (Method RH B).

Stage 2: 1-(1-adamantylmethyl)imidazolidinyl-2-one (c)

MN MNVos ra or M MN po

Solid potassium tert-butoxide (520 mg, 4.634 mmol) was added to the stirred solution of tert-butyl. of M-(2-(1-adamantylmethylamino)ethylcarbamate (470 mg, 1.524 mmol) in anhydrous tetrahydrofuran (13 mL) under a nitrogen atmosphere, and the reaction mixture was heated at 70 °C for 13 h. The heterogeneous mixture was allowed to cool to ambient temperature, it was acidified with hydrochloric acid (6.0 mL, 1.0 M, 6.000 mmol), and the volatiles were removed under reduced pressure.The aqueous residue was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were washed with brine (10 mL ), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 95-10 90 methanol in CH2Cl2 ) to obtain 1-(1-adamantylmethyl)imidazolidinyl-2-one (49 mg, 14 95 ) in the form of an off-white solid. 1TN NMR (400 MHz, Veplepe-ab) b 5.31 (5, 1H), 2.90 (ai, U - 8.9, 6.6 Hz, 2H), 2.83 (5, 2H), 2.73 ( yes, U - 68.7, 6.7 Hz, 2H), 2.06 - 1.98 (t,

ZN), 1.80 - 1.73 (t, ZN), 1.69 (ad, U - 12.4, 2.3 Hz, ZN), 1.61 (a, U - 2.8 Hz, 6Н). MO-IER t/ calc. 234.17322, found 235.2 (M.-1)x; retention time: 1.51 min. (Method of RH B).

Stage 3: (145)-8--3-Cadamantan-1-yl)methyl)|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23 -pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 229) o o o re M p m

M/N | and M | y o y M y i) Y si 4 - o M | - and |, rya m and M M M M

MN by Mi MN

In a bottle of 4 ml (14 5)-8-chloro-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!i 1 7.3.1.111,14.05,10)htetracose-1 ( 23), 5,7,9,19,21-hexane-2,2,4-trione (20 mg, 0.04298 mmol), 1-(1-adamantylmethyl)imidazolidinyl-2-one (13 mg, 0, 05548 mmol) cesium carbonate (52 mg, 0.1596 mmol), xanthophos (4 mg, 0.006913 mmol) and anhydrous dioxane (1.0 mL) were added in the indicated order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. After that, Rag(ava)z (4 mg, 0.004368 mmol) was added under nitrogen and nitrogen was bubbled through the reaction mixture for another 2 minutes and the mixture was sealed under nitrogen. The mixture was stirred at 115°C for 15 h. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0 mL) and filtered through M/paytap syringe disc filter with PTFE 0.45 µm The sample was purified by preparative reversed-phase HPLC-MS (30-99 95 acetonitrile in water (hydrochloric acid as modifier)) to give (145)-8-(3-Cadamantane -1-ylylmethyl|-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1 (22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 229) (12 mg, 43 95) as a yellowish solid. MO-IER t/72 calculations 647.3254, found 648.5 (M.-1) k, retention time: 1.82 min (Method RH 5).

Example 182: Preparation of 23,23-dimethyl-11-(3-2-(11-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16 ,22-pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 236)

o (c) (c) c Vier1 o Zir? M ZierZ NM Zer4 / Vosm Vier5 ohm on on on

KYA KU (vol

Vosm Viverbv Vosm v Z Wirt tsk? s s ono beev

What What And ZhK o. and MM SI

OM mn, E Mn KT va

Kt

HER M Oh -x S | Me vier9 uva Zh vivoto 5-07 MU cho -Kh o u MU o --x -K sh- mn KT va Mn

ОМ сх т | oh oh dm Mk -

CT and Mn

Stage 1: 4-(1-methyl-1-nitroethyl)tetrahydropyran-2-one o c) su Y

OHM

5 5,b-dihydropyran-2-one (50 g, 510 mmol) and 1,8-diazabicyclo(|5.4.F)undec-7-ene (7.6 ml, 51 mmol) were dissolved in 2-nitropropane (138 ml, 1530 mmol), and the resulting mixture was heated to 100 "s for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated by massio to remove excess volatiles. The remaining oil was dissolved in ethyl acetate (1 L ) and extracted with 1 M hydrochloric acid (100 mL) and water (100 mL). The aqueous phases were discarded, and the organic phase was dried over sodium sulfate, filtered, and concentrated in oil to give 4-(1-methyl-1-nitroethyl)tetrahydropyran- 2-one (85 g, 79 o) in the form of an orange solid. The method of РХ R).

Stage 2: 4-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (c) (c) (c) with NM

OM on

4-(1-methyl-1-nitroethyl)tetrahydropyran-2-one (85 g, 454 mmol) was dissolved in ethanol (1.2 L), then Raney nickel (10 g, 170 mmol) was added, and the resulting suspension was hydrogenated at 2 bar H 2/80 "C for 25 hours. The reaction mixture was filtered, the sediment on the filter was discarded, and the filtrate was returned to the reactor and heated to 120 "C for 23 hours. The mixture was concentrated to an oil in vacuo to give 4-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (63.5 g, 89,905) as a pale yellow solid. MO-IER ip/2 calc. 157.00, found 158.20 (Ma1)w; retention time: 1.30 min. (The method of RH R).

Stage 3: 2-(2,2-dimethylpyrrolidin-3-yl)-ethanol (c) q. - what

OH one 4-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (63.5 g, 404 mmol) was dissolved in tetrahydrofuran (2 L). Lithium aluminum hydride (61.3 g, 1616 mmol) was added in small portions and the resulting suspension was heated under reflux under a nitrogen atmosphere for 45 hours, cooled to room temperature and carefully quenched with saturated sodium sulfate solution (300 mL). The mixture was diluted with MTBE (1 L) and filtered. The precipitate on the filter was discarded, and the filtrate was dried over sodium sulfate, filtered, and concentrated to give 2-(2,2-dimethylpyrrolidin-3-yl)ethanol (50.8 g, 87 95) as a pale yellow oil. MO-

IER t/2 calc. 143.00, found 144.20 (Ma-1)zh4; retention time: 0.68 min. (The method of RH R).

The crude product was used without further purification.

Stage 4: 3-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester. 2-(2,2-dimethylpyrrolidin-3-yl)ethanol (50.8 g, 355 mmol) was dissolved in a mixture of dichloromethane (350 mL) and water (350 mL). Sodium bicarbonate (59.6 g, 710 mmol) and di-tert-butyl dicarbonate (73.6 g, 337 mmol) were added and the resulting mixture was stirred at room temperature for 19 hours. Sodium hydroxide (14 g, 350 mmol) and water (50 mL) were then added, and the mixture was stirred at room temperature for 18 h, then diluted with diethyl ether (1 L). The phases were separated and the aqueous phase was extracted with diethyl ether (2 x 350 mL). The aqueous phase was discarded, and the combined organic phases were dried over sodium sulfate, concentrated and then triturated with hexane. The resulting pale yellow solid was collected under vacuum

With filtration to obtain tert-butyl ether 3-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid (60.0 g, 69 95) in the form of a pale yellow solid. MSO-IER t/2 calculation . 243.00, found 244.00 (M-1) k; retention time: 4.24 min. (The method of RH R).

Stage 5: tert-butyl ester of 3-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid

VosmM Vosii ---- he om

3-(2-Hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ether (54.5 g, 224 mmol) was dissolved in dichloromethane (545 mL). Triethylamine (62.5 mL, 448 mmol) was added and the resulting solution was cooled in an ice water bath, then methanesulfonyl chloride (19.2 mL, 247 mmol) was added dropwise over 1 hour. The ice bath was then removed and the reaction mixture was stirred for 1 h at room temperature, and then quenched with saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the organic phase was extracted with water (2 x 200 mL). The aqueous phases were discarded, and the organic phase was dried over sodium sulfate, filtered and concentrated to obtain 3-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ether (72.2 g, quantity) like orange oil. MO-IER t/2 calc. 321.00, found 322.20 (M.-1); retention time: 5.24 min. (The method of RH R).

Step 6: 3-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester ----- oem more

3-(2-Methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ether (10.0 g, 31.1 mmol) was dissolved in 1,4-dioxane (100 mL). 28 95 ammonium hydroxide (100 mL) was added and the reaction mixture was heated to 40 "C in a Parr reactor for 26 hours. 1,4-dioxane was removed in vacuo and the remaining material was extracted with dichloromethane (2 x 100 mL). The phases were separated, the aqueous phase was discarded, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to np.The remaining yellow oil was purified by silica gel chromatography (0 95-15 95 methanol in dichloromethane gradient) to give tert-butyl ether 3-(2 -aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid. (5.1 g, 68 95) in the form of a pale yellow solid. MO-IER n/7 calculated 242.00, found 243.20 (M --1)k, retention time: 3.09 min (Method RH R).

Stage 7: tert-butyl 2,2-dimethyl-3-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate) o, o o

VosmM ra - Z y nm | nm | incl

M ikh M. 02

E many, MN

VosmM

To 3-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ether (500 mg, 2.063 mmol) and b-fluoropyridine-2-sulfonamide (363.4 mg, 2.063 mmol) in dimethyl sulfoxide (4.21 ml) was added potassium carbonate (290.8 mg, 2.104 mmol) and the mixture was stirred at 100 °C for 20 h, then allowed to cool to room temperature.

It was diluted with ethyl acetate and poured into saturated aqueous MIN4Cl. The layers were separated, then the organic layer was washed with a saturated aqueous saline solution, dried (sodium sulfate),

Zo was filtered and concentrated to a yellow foam, which was purified by silica gel chromatography using a slight gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl 2,2-dimethyl-3-(2-((b-sulfamoyl-2-pyridyl )amino|ethyl|pyrrolidine-1-carboxylate (497.5 mg, 61 95) as a white solid, MO-IER Ip/2 calcd 398.19876, found 399.1 (M--1)-k; retention time: 0.58 min (method RH A).

Stage 8: tert-butyl 3-(2-C6-C2-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2- pyridylamino|ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

KU (Y school

Mykh M - M - M o- TM M si o- M si

Mn CT and CT and Mn

Co Co 2-chloro-6-I3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (499.7 mg, 1.330 mmol) and carbonyldiimidazole (269.8 mg , 1.664 mmol) (recrystallized from tetrahydrofuran) was combined in tetrahydrofuran (6.89 mL) and stirred for 60 min at room temperature. Tert-butyl-2,2-dimethyl-3-(2-(b- sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-i-carboxylate (530 mg, 1.330 mmol) in tetrahydrofuran (2.65 mL), then 1,8-diazabicyclo/5.4.O)undec-7-ene (1.013 g , 6.654 mmol), and the reaction mixture was stirred at room temperature for 16 h.

Tetrahydrofuran was removed using a rotary evaporator, the residue was dissolved in ethyl acetate and washed with 6 n. hydrochloric acid (1X), then with saline solution (1X), dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a 2759 C18 reversed-phase column, eluting with a gradient from 50 95 to 10095 acetonitrile in water to obtain / / tert-butyl-3-(2-((6-(2-chloro-6-I(3-(2-1P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl |-2-pyridylamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (497.5 mg, 49 95) as a white solid, NMR (400 MHz, DMSO-ab) b 12.75 (5, 1H) . . 7.1 Hz, 2H), 3.25 (5, 2H), 3.02 (4.9 - 91 Gu, 1H), 2.09 (1, U - 7.1 Hz, 2H), 1.90 - 1.57 (t, 4H), 1.41 - 1.31 ( t, 11), 1.29 (5, 2H), 1.19 (y, 9 - 1.7

Gu, 1H), 0.98 (y, U - 5.1 Hz, 2H), 0.96 (y, U - 4.2 Hz, ЗН), 0.89 (a, U - 5.1 Hz, 2H). MO-IER t/ calc. 1755.248, found 756.1 (M--1) k; retention time: 0.84 min. (Method of RH A).

Stage 9: 2-chloro-N-(6-(2-(2,2-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl|)-6-(3-(2-

P-"(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxamide c)

M p KU y S y uv y 5-07 MA s Sh-s (in) dm Meiv

CT -- MN CT and MN

KU schi

tert-butyl 3-(2-C6-Ce-chloro-6-I3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylamino|ethyl |-2,2-Dimethylpyrrolidine-1-carboxylate (498.6 mg, 0.6593 mmol) was dissolved in dichloromethane (2.176 mL) and trifluoroacetic acid (2.032 mL, 26.37 mmol) was added to the mixture, and the mixture was stirred at room temperature. temperature for 60 min. The mixture was concentrated to dryness under reduced pressure and processed

With saturated aqueous sodium bicarbonate and ethyl acetate and the layers were separated. (The solubility of the product in ethyl acetate under these conditions is very low, the addition of methanol helps). The ethyl acetate layer was washed with n. hydrochloric acid, then dried (sodium sulfate), filtered and concentrated the organic layer by rotary evaporation followed by drying with oil, obtaining 2-chloro-M-I((6-(2-(2,2-dimethylpyrrolidin-3-yl) /ethylamine|-2-pyridyl| sulfonyl|-6-

13-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (351.2 mg, 81 95) as a white solid. MO-IER t/2 calc. 655.19556, found 656.1 (M--1)k; retention time: 0.58 min. (Method of RH A).

Stage 10: 23,23-dimethyl-11-(3-(2-(/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16 , 22-pentaazatetracyclo|16.3.1.15,8.09,14|gricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 236)

(0)

In POM

M. - M | N o shoTm M si M y M i ko; MN shchi

Combined 2-chloro-M-((6-(2-(2,2-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl/|-6-

I3-(2-P1-"trifluoromethyl)cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (351.2 mg, 0.5353 mmol), potassium carbonate (369.8 mg, 2.676 mmol), molecular ZA sieves and dimethylsulfoxide (21.3 ml) in a flask purged with nitrogen, closed, heated to 180 "C and stirred for 18 hours. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, and after -- saline solution.

The organic layers were separated, dried over sodium sulfate and evaporated, then purified by chromatography on silica gel using a gradient from 10095 hexanes to 100 95 ethyl acetate (the product is eluted after reaching 100 95 ethyl acetate) to obtain 23,23-dimethyl-11- (3-12-(/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-17A6-thia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15,8.09,14 |gricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (compound 236) (5.7 mg, 2 90). MO-IER t/72 calc. 619.2189, found 620.1 (M'-1) t; retention time: 2.08 min. (Method of RH B).

Example 183: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(C4-(trifluoromethyl)cyclohexyl|methyl)imidazolidinyl-1-yl)-2A6b-thia-3,9,11, 18,23- pentaazatetracyclo!17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 239) sno му и м иВос и МНВос зер гу" вы

Same in 3 all o o o o o o o i o -ha i

Hu 4 tn M M MN ge as M pod Kut pod sizlgap5 igoteg 2 go

Stage 1: tert-butyl M-(2-(4-(trifluoromethyl)cyclohexyl|methylamino|ethyl Icarbamate)

N ia it Du MNVos

HU Nom Gas

To a stirred solution of 4-(trifluoromethyl)cyclohexanecarbaldehyde (250 mg, 1.388 mmol) in anhydrous methanol (10 mL) was added a solution of tert-butyl-N-(2-aminoethyl)carbamate (223 mg, 1.392 mmol) in anhydrous methanol (1 mL ) in a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 h, it was cooled to 0 °C (ice bath). Sodium borohydride (112 mg, 2.960 mmol) was then slowly added in two portions, the mixture was allowed to warm to ambient temperature, and stirring was continued. for 15 h. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aq.

From sodium bicarbonate (2 x 15 ml) and saline solution (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl M-(2-|(4-(trifluoromethyl)cyclohexyl|methylamino|ethylcarbamate) (400 mg, 89 95) in the form of a yellow gum.

The crude material was used in the next stage without additional purification. MO-IER t/2 calc. 324.20245, found 325.3 (M--1) k; retention time: 0.9 min. (Method of RH B).

Stage 2: 1-(4-«(trifluoromethyl)cyclohexyl|methylimidazolidinyl-2-one (cis/trans isomer 2)

(in)

МНВос ХХ ша M МН ж ХУ у г гзс sizlLgap isoteg 2

Solid potassium tert-butoxide (270 mg, 2.406 mmol) was added to a stirred solution of tert-butyl-N-(2-(4-trifluoromethyl)cyclohexyl|methylamino|ethylcarbamate (260 mg, 0.8015 mmol) in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere, and the reaction mixture was heated at 70°C for 13 h. The heterogeneous mixture was allowed to cool to ambient temperature and then acidified with aqueous hydrochloric acid (3.0 mL, 1.0 M, 3.000 mmol) and the volatiles were removed substance under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC-MS with reversed phase (0-70 95 acetonitrile in water (hydrochloric acid as a modifier) with obtaining as the second cis/trans isomer for elution, 1-D(α-(trifluoromethyl)cyclohexyl|methylimidazolidinyl-2-one (cis/ trans-isomer 2) (52 mg, 26965) in in the form of an off-white solid. 1H NMR (400 MHz, Veplepe-ab) b 4.93 (5, 1H), 2.89 (y, 9 - 7.2 Hz, 2H), 2.77 - 2.63 (t, 4H), 1.80 (aa, 9 - 13.4, 3.6 Hz, 2H), 1.72 - 1.57 (t, 1H), 1.52 (da, U - 13.4, 3.5 Hz, 2H), 1.22 - 1.06 (t, ЗН), 0.66 (da, y - 13.3, 3.6 Hz, 2H). MO-IER t/: calc. 250.1293, found 251.2 (M.-1) housing; retention time: 1.3 min. (Method of RH B).

Stage C: (145)-12,12-dimethyl-8-(2-oxo-3-Ca-(trifluoromethyl)cyclohexyl|methyl)imidazolidinyl-1-yl)-2A6b-thia-3,9,11,18, 23- pentaazatetracyclo!|17.3.1.111,14.05,10)|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 239) o o o o ooo

Х хх ра Хе в: ад яMoreover, ЯМ - каА

M M M Mn es i s M I should do sizlgapz isoteg 2 es

In a vial, (145)-8-chloro-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloly 1 7.3.1.111,14.05,10)htetracose-1 (23), 5,7,9,19,21-hexane-2,2,4-trione (20 mg, 0.04445 mmol), 1-(4-(trifluoromethyl)cyclohexyl|methylimidazolidinyl-2-one (13 mg, 0, . Rag(ava)z (4 mg, 0.004368 mmol) was added under nitrogen and the mixture was purged with nitrogen for another 2 min, then blocked under nitrogen.

From at 108 7C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). The volatiles were removed under reduced pressure, and the residue was dissolved in dimethylsulfoxide (1.5 mL) and filtered through a 0.45 μm PTFE M/paytap syringe disc filter. The sample was purified using preparative reversed-phase HPLC-MS (3095 -99 95 acetonitrile in water (hydrochloric acid as a modifier) to obtain (145)-12,12-dimethyl-8-(2-oxo-3-

C4-(trifluoromethyl)cyclohexyl|methyl)imidazolidinyl-1-yl)-2A6-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5 ,7,9,19(23),20-hexane-2,2,4-trione (Compound 239) (9 mg, 31 95) as a yellowish solid. This compound is a single isomer of unknown cis- or trans-orientation on the cyclohexane ring. TN NMR (400

MgGu, DMOO-ab) b 12.26 (5, 1H), 7.59 (y, U - 8.6 Hz, 1H), 7.58 - 7.53 (t, 1H), 7.40 (aa, 9 - 8.6, 2.7

Hu, 1), 7.06 - 7.01 (t, 1H), 6.94 (a, 9 - 68.7 Hu, 1H), 6.70 (ad, 9 - 8.5, 0.68 Hz, 1H), 4.01 - 3.83 (t,

ZN), 3.51 - 3.41 (t, ZN), 3.91 - 3.28 (t, 1H), 3.11 - 3.04 (t, 2H), 2.94 (a, U - 13.4 Gu, 1H), 2.70 (1.9 - 0.8 Hz , 1H), 2.1841.9 - 8.1 Hu, 1H), 2.13 - 2.01 (t, 1H), 1.95 - 1.80 (t, 4H), 1.79 - 1.74 (t, 2H), 1.58 (5, ЗН), 1.57 - 1.48 (t, ZN), 1.47 (v, ZN), 1.34 - 1.14 (t, ZN), 1.00 (d, U - 12.6 Hz, 2H). 19 E NMR (376 MHz, dimethylsulfoxide-a 6) b -72.24 (d, 9 - 8.9 Hz). MO-IER t/2 calc. 663.28143, found 664.4 (M--1) k; retention time: 2.0 min. (Method of RH B).

Example 184: Preparation of 11-I(3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-7,7-dimethyl-17A6bthia-2,8,10,16,22-pentaazatetracyclo|16.3. 1.15,8.09,14|Itricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (compound 250) (9) (c) o o (c ) kh d

Mach Ver Mach Y 0-Y 7 M oi o X Mn a -- don - dedy o o epapioteg2 (c) i h Ii B z es | n and | and | In | -080- -Us si p Bier4 5-47 Msi Bier Z (c) i I tot -- MN

VosM epapioteg2 epapioteg2 o Kf kh shcha y

N. M. in May

RC yin epapioteg 2 5 Stage 1: tert-butyl 2,2-dimethyl-4-(2-((b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (enantiomer 2) o) o (in )

B xx / y y nm 7 | Name

I have Mach

Ge) (c)

MN x MN you in

Gee! (c) epapioteg 2

Racemic tert-butyl-2,2-dimethyl-4-(2-(b-sulfamoyl-2-pyridyl)amino|ethyl|pyrrolidine-1-carboxylate (1.475 g, 3.701 mmol) was resolved by chiral NRC using

SPpigaiRak b. (Column 250 x 21.2 mm, particle size 5 μm) with 3295 methanol (no modifier))/68 95 carbon dioxide mobile phase at 70 mL/min, giving tert-butyl 2,2-dimethyl as the second enantiomer for elution -4-(2-(b-sulfamoyl-2-pyridyl)amino|ethylpyrrolidine-1-carboxylate (enantiomer 2) (617 mg, 84 95) as a white foam.

MO-ER t/2 calc. 398.19876, found 399.3 (M--1) t; retention time: 1.59 min. (Method of RH B).

Stage 2: tert-butyl 4-(2-((6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|sulfamoyl|-2-pyridylyamino| ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (enantiomer 2)

yah

Ge) zhu shcha --хО о о | N. I

Ba - t i on Dn ME s ho i (in) t IF , 5th i si -0-i- - mn o sh- r Mn VosM v gadi epapioteg2 epapioteg 2

To the flask was added 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridine-3-carboxylic acid (147.7 mg, 04082 mmol), recrystallized carbonyldiimidazole (66.2 mg, 0, 4083 mmol) and tetrahydrofuran (4 ml). The reaction mixture was stirred at 40 "C for 90 minutes. Then tert-butyl-2,2-dimethyl-4-(2-(6b-sulfamoyl-2-pyridyl)amino|ethyl-pyrrolidine-1-carboxylate (enantiomer 2) (130 mg, 0.3262 mmol) followed by the addition of 1,8-diazabicyclo|5.4.0Iundec-7-ene (150 μL, 1.003 mmol). The reaction mixture was stirred overnight. The reaction mixture was filtered and purified by HPLC (30-99 95 acetonitrile in water with 0.1 96 hydrochloric acid modifier) to obtain tert-butyl-4-(2-(6-(2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin- 3-carbonyl|isulfamoyl|-2-pyridylyamino|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 2) (64 mg, 26 95) in the form of a white foam. MO-IER t/2 calc. 741.30756 , found 742.4 (Ma1)k, retention time: 2.19 min (Method RH 5).

Stage C: 2-chloro-6-I3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-((6-(2-(5,5- dimethylpyrrolidin-3-yl)ethylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (enantiomer 2) (c) ха (c) Ба 5 СИ и | хх с и

M. - Mach m. | ru Mach 5-5 me 5-27 My dsh- Mn /- (A tlya- sh- Mn - ts o Y I o epapioteg 2 epapioteg 2

Tert-butyl-4-(2-(6-C2-chloro-6-(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|pyridin-3-carbonyl|Isulfamoyl|-2-pyridylamino) was added to the flask. ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 2) (64 mg, 0.08622 mmol), dichloromethane (5 mL), and trifluoroacetic acid (250 μL, 3.245 mmol).The reaction mixture was stirred for 30 min. evaporated to dryness and neutralized with saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to obtain 2-chloro-6-I(3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl|-M-( (6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (enantiomer 2) (51 mg, 92 95) in the form of a white solid. MO- IER Ip/2 calculated 641.2551, found 642.3 (M'-1)k, retention time: 1.11 min (Method

РХ 5).

Stage 4: 11-3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-7,7-dimethyl-1/Abthia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15, 8.09,14Hygtricose-1 (22), 9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (compound 250)

PO n B

Mo M o already Me o um Mo ih s y teye epapioteg2 epapioteg 2

Potassium carbonate (59 mg, 0.4269 mmol), cesium fluoride (25 mg, 0.1646 mmol), molecular sieves Z A and a solution of 2-chloro-6-(3-(3,3-dicyclopropylpropoxy) were added to the vial. pyrazole -1-yl|-M-

I((6-(2-(5,5-dimethylpyrrolidin-3-yl)ethylamine|-2-pyridyl|sulfonyl|pyridine-3-carboxamide (enantiomer 2) (51 mg, 0.07941 mmol) in dimethyl sulfoxide (3 .5 ml). The reaction mixture was placed in an oil bath preheated to 150 "C and left to stir overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (10-99 95 acetonitrile in water with a modifier of 0.195 hydrochloric acid) , obtaining 11-I3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl|-7, 7-dimethyl-1 7Abthia-2,8,10,16,22-pentaazatetracyclo|16.3.1.15,8.09, 14Hygtricose-1(22),9,11,13,18,20-hexane-15,17,17-trione (enantiomer 2) (compound 250) (14.1 mg, 29 95). MO-IER t/2 calculated 605.27844, found 606.4 (M.-1T) zhk, retention time: 1.9 min (method RH b).

Example 185: Preparation of (145)-8-I3-(2-idispiro|2.0.2.1|heptan-7-yl-2-oxoethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6- thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4 -trion (Compound 258) oh

And ra hu and meh Z o m | same M zier4 o do sa s M i - 2 si I iv jan - voru

Stage 1: 1-dispiro(2.0.2.1|heptan-7-yl-2-(1H-pyrazol-33-yloxy)ethanone. o (c) (c)

In about M

MVos (-- - z» and n -

Tert-Butyl-3-(2-dispiro|2.0.2.1|heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (350 mg, 0.7256 mmol) was dissolved in dichloromethane (2.31 mL) with trifluoroacetate acid (1.241 g, 10.88 mmol), and the reaction mixture was stirred at room temperature for 60 min. The reaction mixture was evaporated and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous part was extracted two more times with ethyl acetate, then the organic layers were combined, washed with saline solution, dried over sodium sulfate, filtered and evaporated to obtain an oil, 1-dispiro(2.0.2.1|Iheptan-7-yl-2. -(1H -pyrazol-3-yloxy)ethanone (223.7 mg, 93 95). MO-IER mp/2 calcd 218.10553, found 219.0 (M--1)k; retention time: 0.43 min. (Method of RH A).

Stage 2: tert-butyl 2-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-yl-2-oxo-ethoxy)pyrazol-1-yl|pyridine-3-carboxylate (6) where (c) (c) o M o.

SI SI

Tert-butyl 2,6-dichloropyridine-3-carboxylate (134.3 mg, 0.5413 mmol), 1-dispiro|2.0.2.1|heptan-7-yl-2-(1H-pyrazol-3-yloxy)ethanone (179.1 mg, 0.5416 mmol) and potassium carbonate (89.88 mg, 0.6503 mmol) were combined in anhydrous dimethyl sulfoxide (2.362 mL).

1,4-diazabicyclo|2.2.2|octane (12.16 mg, 0.1084 mmol) was added and the heterogeneous mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (4.542 mL) and stirred for 15 min. The resulting white solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give tert-butyl-2-chloro-6-I(3-(2-dispiro|2.0.2.1|heptan-7-yl-2-oxoethoxy)pyrazol-1-yl|Ipyridine-3-carboxylate (148.7 mg, 64 95) as a white solid. MO-IER t/2 calcd. 429.14554, found 430.0 (Ma-1)-; Retention time: 0.83 min. (Method RH A ).

Stage 3: 2-chloro-6-3-(2-dispiro|2.0.2.1)heptan-7-yl-2-oxo-ethoxy)pyrazol-1-yl| pyridine-3-carboxylic acid o (c)

Seh se (6) M o what; MU s o ct al sh-shoo -- --

Tert-butyl 2-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-yl-2-oxoethoxy)pyrazol-1-yl|pyridine-3-carboxylate (145.7 mg, 0.3389 mmol) was dissolved in dichloromethane (1.457 mL) with trifluoroacetic acid (391.7 µL, 5.084 mmol) and the reaction mixture was stirred at room temperature for 2.5 h. Volatiles were removed by rotary evaporation (no heat) followed by 30 min drying in vacuo The crude material was purified by silica gel chromatography using a shallow gradient from 100 95 dichloromethane to 2095 methanol in dichloromethane to give 2-chloro-6-I(3-(2-dispiro|2.0.2.1|heptan-7-yl- 2-oxoethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (89.6 mg, 7195) in the form of a brown solid contaminated with a small amount of starting material, which was immediately sent to the next stage. 373.08295, found 374.0 (M--1)k Retention time: 0.61 min (RH Method A).

Stage 4: tert-butyl (45)-4-III3-C(6-Ce-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-yl-2-oxo-ethoxy)pyrazole-1 -yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl- pyrrolidine-1-carboxylate о ох 79 Х хи? рек Хх muх ув Хо ів о m s Ів (c) | y Mi - same shk; M si - - M Gei) 7 -sh- MH 2g-xchloro-6-3-(2-dispiro|2.0.2.1|heptan-7-yl-2-oxoethoxy)pyrazol-1-yl |Ipyridine-3-carboxylic acid (89.6 mg, 0.2397 mmol) and carbonyldiimidazole (48.63 mg, 0.2999 mmol) (freshly recrystallized from tetrahydrofuran) were combined in tetrahydrofuran (1.165 mL) and

The mixture was stirred for 45 min at room temperature. Then tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (98.89 mg, 0.2397 mmol) in tetrahydrofuran was added (448 μL), followed by 1,8-diazabicyclo/5.4.0undec-7-ene (179.3 μL, 1.199 mmol), and the reaction mixture was stirred at room temperature for 16 hours.

Tetrahydrofuran was removed using a rotary evaporator, then dissolved in ethyl acetate and washed with 1 N. hydrochloric acid (1X) and brine (1X), dried (magnesium sulfate), filtered and concentrated to a light brown oil, which was purified by silica gel chromatography using a fine gradient from 100 95 dichloromethane to 20 95 methanol in dichloromethane, resulting in poor separation of the product from the two starting materials. Then the material was filtered and purified using the reversed-phase HPLC-MS method (column I spike C 18 (2) (75 x 30 mm, particle size 5 μm), which is sold

Rpepotepeh (art.: 00 "Sb-4252-00-АХ). and a double gradient from 1 o to 9995 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile , flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 25723) to obtain tert-butyl (4 5)-4-(3-((6-Ce-chloro-6-I3-( 2-dispiro|2.0.2.1|)heptan-7-yl-2-oxoethoxy)pyrazol-1-yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl/|-2,2-

dimethylpyrrolidine-1-carboxylate (49.5 mg, 27 95). MO-IER t/2 calc. 767.2868, found 768.1 (MA1) k; Holding time: 0.83 min. (Method of RH A).

Stage 5: 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|-2-pyridylI|sulfonyl|-6-I3-(2-dispiro|2.0. 2.1|heptan-7-yl-2-oxo-ethoxy)pyrazol-1-yl|Ipyridine-3-carboxamide (trifluoroacetate salt) (9)

Ge) vu uch va ch vash with "I ke

X what, M si I what; We are -Kh 7 - eight mn nm y

Tert-butyl (45)-4-IZ-K(6-Ce-chloro-6-I3-(2-dispiro(2.0.2.1|heptan-7-yl-2-oxoethoxy)pyrazol-1-yl|pyridin- 3-Carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (49.5 mg, 0.06443 mmol) was dissolved in dichloromethane (1.5 mL) and cooled to 0 "C and trifluoroacetic acid (49.64 μL, 0.6443 mmol) was added dropwise to the mixture, and the mixture was stirred at 0 "С for 60 minutes. Trifluoroacetic acid (49.64 μL, 0.6443 mmol) was added dropwise at 0 "С , then heated to room temperature and stirred for 30 minutes, re-cooled to 0 "C, trifluoroacetic acid (49.64 μl, 0.6443 mmol) was added, heated to room temperature and stirred for 20 minutes. Then trifluoroacetic acid (49 .64 μL, 0.6443 mmol) at room temperature and stirring was continued at room temperature for 1 h. The mixture was concentrated to dryness on a rotary evaporator without heat. Evaporate with ether (5X), then place in vacuo for 1 g one, obtaining 2-chloro-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|-2- pyridyl|sulfonyl|-6-(3-(2-dispiro|2.0 .2.1|heptan-7-yl-2-oxoethoxy)pyrazol-1-yl|pyridine-3-carboxamide (trifluoroacetate salt) (50.4 mg, 100 95) as a white solid. MO-IER t/72 calc. 667.2344, found 668.1 (M--1) k; retention time: 0.55 min. (Method of RH A).

Stage 6: (145)-8-I3-(2-y(dispiro(2.0.2.1|heptan-7-yl-2-oxoethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2A6b- thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4- trione (Compound 258)

Yee hee Pooh o

Uh M x xx m7? 5 x maidens: - x m s she, m si -- -x shcha; WE --x

TRA

Combined 2-chloro-M-(6-I3-((35)-5,5-dimethylpyrrolidine-3-yl|Ipropylamino|-2-pyridyl|sulfonyl|-6-(3-(2-dispiro|2.0.2.1 |heptan-7-yl-2-oxoethoxy)pyrazol-1-yl|pyridin-3-carboxamide (trifluoroacetate salt) (50.4 mg, 0.06443 mmol), potassium carbonate (53.43 mg, 0.3866 mmol ), molecular sieves Z A and dimethylsulfoxide (3.057 mL) in a vial purged with nitrogen,

Capped, heated to 155°C and stirred for 18 hours. Cooled to room temperature, and the mixture was filtered, diluted with ethyl acetate and 1 N hydrochloric acid, and the layers were separated. The aqueous layer was washed again with ethyl acetate, and the organic layers were combined, washed with brine (them), dried (magnesium sulfate), filtered and concentrated to a brown solid, which was purified by chromatography on silica gel using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate to give (14.5)-8-I3- (2-ydispiro|2.0.2.1|heptan-7-yl-2-oxoethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab-thia- 3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,1O|hetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (11 mg), which was still contaminated For further reaction, this material was dissolved in methanol (110 μL) at room temperature and Mmavn (1.646 mg, 0.04351 mmol) was added (strong bubbling was noted) and the resulting solution was stirred for 10 minutes, then concentrated on a rotary evaporator. The residue was dissolved in dimethylsulfoxide, filtered and purified using the reversed-phase HPLC-MS method using a commercially available Ipa C 18 column (2) (75 x 30 mm, particle size 5 μm)

Rpepotepeh (рп: 00 "С-4252-0О0-АЧ) and a double gradient from ЗО bo to 99 95 mobile phase B for 15.0 min (mobile phase A - water (5 mM hydrochloric acid), mobile phase B - acetonitrile, flow rate - 50 ml/min, injection volume - 950 μl and column temperature - 257С2)) with obtaining as a reduced starting material during the reduction (14.5)-8-I3-(2-

ydispiro(2.0.2.1|heptan-7-yl-2-oxoethoxy)-1H-pyrazol-1-yl|-12,12-dimethyl-2Ab6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (compound 258) (2.20 mg, 20 95 ) in the form of a white solid. MO-IER n/7 calc. 631.2577, found 632.2 (M--1) k; retention time: 1.99 min. (Method of RH B).

Example 186: Preparation of (145)-12,12-dimethyl-8-(2-oxo-3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1,2-dihydropyridin-1-yl)-2A6-thia -3,9,11,18,23-pentaase tetracyclo| 1 7.3.1.111,14.05,10|htetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 268) (c) o AH no mno bbeii 00 tpvvo what" ss vier2 w | -5 si si (9) tank -

Es OoM5 ze po | M MA choi t KO - o B 7 z o 5 on pom vs o | r x M ikh vir 4 ko | m M si I -- - zhsh db

VosM (9) oh Gi 9570 skh 7 z Z es. Ge) Y | - th I ru zier 5 p uva | and and KO | MTM tei yad basa M - MN | ro Ada sei

Stage 1: 3-I(-tert-butyl (dimethyl)silyl|oxy-1H-pyridin-2-one o (c) no tv5o

MN with | MN rya rya

3-Hydroxy-1H-pyridin-2-one (1 g, 9.001 mmol) and imidazole (1.6 g, 23.50 mmol) were suspended in

M,M-dimethylformamide (10 ml) in an inert atmosphere. A solution of tert-butylchlorodimethylsilane (1.5 g, 9.952 mmol) in M,M-dimethylformamide (10 mL) was added dropwise at room temperature over 30 minutes. The reaction mixture was then allowed to stir overnight. Then the resulting solution was poured into water and the mixture was extracted with tert-butyl methyl ether (3 x 50 ml). The combined organic layers were washed with water, brine, then dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give 3-Egret-butyl(dimethyl)silyl|oxy-1H-pyridin-2-one (1.8 g, 89 95) as a light brown solid, which was used directly in the next reaction. IN NMR (400 MHz, Spiogotogpt-a) b 6.97 (go, U - 6.4, 1.6, 0.8 Hz, 1H), 6.89 (aa, U - 7.2, 1.68

Gu, 1H), 6.14 (ai, 9 - 7.2, 6.5 Hz, 1H), 1.00 (a, U - 1.3 Hz, 9H), 0.26 (5, 6H).

Stage 2: tert-butyl 2-chloro-6-(3-hydroxy-2-oxo-1-pyridyl)pyridine-3-carboxylate

MN nina ko! - -dy SI SI | M M SI no

A mixture of tert-butyl 2,6b-dichloropyridine-Z-carboxylate (1 g, 4.031 mmol), Z-Egret-butyl(dimethyl)silyl|oxy-1H-pyridin-2-one (910 mg, 4.038 mmol) potassium carbonate (1.32 g, 9.551 mmol) and 1,4-diazabicyclo|2.2.2|octane (112 mg, 0.9985 mmol) in dimethyl sulfoxide (10 mL) were stirred at room temperature for 15 hours. The reaction mixture was poured onto crushed ice, the resulting precipitate was collected by filtration and dried to obtain tert-butyl-2-chloro-6-(3-hydroxy-2-oxo-1-pyridyl)pyridine-3-carboxylate (0.82 g, 63 95) in the form of a light brown solid. IN NMR (400 MHz, Spiogoitogtt-4) b 12.57 (5, 1H), 8.15 (a, U - 8.6 Hz, 1H), 7.36 (ai, U - 7.2, 1.8 Hu, 1H), 7.23 (da, U - 6.6, 1.68 Hz, 1H), 6.95 (a, U - 8.3 Hz, 1H), 6.2941.9 6.9 Hz, 1H), 1.59 (5, 9H). MO-IER t/2 calc. 322.07202, found 323.14 (M--1) same; retention time: 0.55 min. (Method РХ 0).

Stage 3: 2-chloro-6-(2-oxo-3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|-1-pyridyl|pyridine-3-carboxylic acid (9) (9) o A o ech o ES OM5 en OV no r M M SI ah kto udrya

A mixture of 2-P1-"trifluoromethyl)cyclopropyl". ethyl methanesulfonate (362 mg, 1.559 mmol), tert-butyl 2-chloro-6-(3-hydroxy-2-oxo-1-pyridyl)pyridine-3-carboxylate (500 mg, 1.549 mmol), cesium carbonate (1.1 g, 3.376 mmol) in dimethylsulfoxide (10 ml) was stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with ethyl acetate.

The combined extracts were washed with saline and water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (0 95-80 95 ethyl acetate in hexane) and the second regioisomer was isolated for elution, and to this material was added trifluoroacetic acid (1.5 mL, 19.47 mmol) and dichloromethane (5 mL) at room temperature. temperature with stirring for 2 hours followed by evaporation of volatile substances to obtain 2-chloro-6-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|-1-pyridyl|pyridine-3-carbon acid (120 mg, 19,965). "IN NMR (400 MHz, Spioghotopt-a) b 8.14 (a, 9 - 8.4 Hz, 1H), 7.28 (9, U - 7.2, 1.9 Hz, 2H), 6.95 (y , U - 8.4 Hz, 1H), 6.22, - 7.1 Hz, 1H), 4.13 (1, 7 - 7.3 Hz, 2H), 2.01 (0.9 7.2 Hz, 2H), 1.58 (5, 9H), 1.01 - 0.87 (t, 2H), 0.69 - 0.57 (t, 2H). MO-IER t/2 calculated 402.05942, found 403.13 (M--1)k; retention time: 0.56 min. (Method RH A).

Stage 4: tert-butyl (45)-4-I3-((6-C(2-chloro-6-(2-oxo-3-(2-P1-"trifluoromethyl)cyclo

Zo propylethoxy|-1-pyridyl|pyridine-3-carbonyl|sulfamoyl|-2-pyridylamino|propyl|-2,2-dimethyl- pyrrolidine-1-carboxylate (9) (9) o

Ii pr z i

And | o y: M y

M M SI kto WE in y "y | ru MN dy

VosmM and

VosmM

In a bottle with a volume of 20 ml tert-butyl-2-chloro-6-(2-oxo-3-(2-(1-(trifluoromethyl)cyclopropyl|ethoxy|-1-pyridyl|Ipyridine-3Z-carboxylate) (100 mg , 0.2483 mmol) and carbonyldiimidazole (47 mg, 0.2899 mmol) were combined in tetrahydrofuran (2 mL) and stirred at room temperature for 2 hours. Tert-butyl (45)-2,2-dimethyl- 4-|3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine-1-carboxylate (114 mg, 0.2763 mmol) followed by the addition of 1,8-diazabicyclo/5.4.Oundec-7-ene (50 µL, 0.3343 mmol) and the reaction mixture was stirred for 16 hours.The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:11 saturated aqueous ammonium chloride/saline solution.

The organic phases were separated, dried over sodium sulfate, filtered and evaporated.

The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100 95 hexanes to 100 95 ethyl acetate to give tert-butyl (45)-4-

IZ-Kb-Ce-chloro-6-(2-oxo-3-(2-11-(trifluoromethyl)cyclopropyl|ethoxy|-1-pyridyl|pyridine-3-carbonyl|isosulfamoyl|-2-pyridylyamino|Ipropyl|- 2,2-Dimethylpyrrolidine-i-carboxylate (48 mg, 24 95). MO-IER t/2 calcd. 796.2633, found 797.4 (M--1)x; Retention time: 0.81 min. ( The RH method

AND).

Stage 5: (145)-12,12-dimethyl-8-(2-oxo-3-2-11-(trifluoromethyl)cyclopropyl|ethoxy)-1,2-dihydropyridin-1-yl)-2A6-thia-3 ... 268)

Gi (c) (c) and c) and | o y: M s

ES o - M y | N

M M si vs Ge) - M 2 d Mn | Ah, t Mn sei

Solution of tert-butyl (45)-4-I3-C(6-Ce-chloro-6-(2-oxo-3-(2-P1-(trifluoromethyl)cyclopropyl|ethoxy|- 1-pyridyl|pyridine-3- carbonyl|sulfamoyl|-2-pyridylyamino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (48 mg, 0.06020 mmol) in dichloromethane (400 μL) and trifluoroacetic acid (100 μL, 1.307 mmol) were stirred at at room temperature for 4 h. The solvents were removed by evaporation and dissolved in ethyl acetate. This solution was washed with 2 mL of saturated sodium bicarbonate solution, and the organic layer was collected, the solvent was removed by evaporation, then dried in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (5 mL), molecular weight 3 A sieves and the reaction mixture was stirred for 10 min. Then cesium fluoride (36 mg, 0.2370 mmol) and potassium carbonate (31 mg, 0.2243 mmol) were added, and the reaction mixture was heated at 150 °C for 16 hours. the mixture was filtered through a U/Layitap disc filter (rigadibs 25 TE) and the filtrate was purified by reversed-phase HPLC-MS using a double gradient nta from 30 9o to 99 9o of mobile phase B for 15.0 min (mobile phase A - water (0.05 95 hydrochloric acid), mobile phase B - acetonitrile) to obtain (145)-12,12-dimethyl-8- (2-oxo-3-12-11-(trifluoromethyl)cyclopropyl|ethoxy)-1,2-dihydropyridin-1-yl)-2A6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111 ,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (compound 268) (19.5 mg, 49 95) in the form of dirty - white solid. 1H NMR (400

From MHz, Spiogoitogp-4) b 7.96 (a, U - 8.4 Gu, 1H), 7.59 (5, 1H), 7.46 (a, 9 - 6.7 Hz, 1H), 7.21 (1.9 - 68.4

Hu, 2H), 6.72 (5, 1H), 6.43 (a, U -8.3 Hz, 1H), 6.21 (I, 7 - 7.0 Hu, 1H), 4.06 (5, 2H), 3.86 (Bg5, 1H), 3.29 - 3.13 (t, 2H), 2.89 (rg5, 1H), 2.36 (Brg5, 1H), 1.95 (I, U - 7.8 Hz, 2H), 1.85 (Bg5, 1H), 1.67 - 1.54 (t, ZN) . MO-IER t/2 calc. 660.2342, found 661.4 (M--1) k; retention time: 1.83 min. (Method of RH B).

Example 187: Preparation of 19,19-dimethyl-4-(3-13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21 -pentaazatetracyclo|15.2.1.111,14.02,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (Compound 273)

we

Vosm 5ier 1 Vosim OM AT enter ber n b o i sun,

What U 5 OH vier3

Me--ki I | sli

M - (9)

N | «er 4 N | vision 5 a pev; shevashya, (9) to and hu -Zh

M - M--mi

Stage 1: tert-butyl 2,2-dimethyl-4-(2-methylsulfonyloxyethyl)pyrrolidine-1-carboxylate

VosM VosmM o ze

Tert-butyl-4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylate (751 mg, 3.086 mmol), dichloromethane (10 mL) and triethylamine (1.75 mL, 12.56 mmol) were added to the flask. . The reaction flask was cooled to 0 "C, and then methanesulfonyl chloride (290 μl, 3.747 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 45 minutes. The reaction was quenched with ice water. The reaction mixture was extracted twice with dichloromethane, dried over sodium sulfate , filtered and evaporated, obtaining tert-butyl-2,2-dimethyl-4-(2-methylsulfonyloxyethyl)pyrrolidine-i-carboxylate (980 mg, 9995) in the form of a thick yellow oil. MSO-IER t/2 cal. 321, 16098, found 322.1 (M-a-1)k, retention time: 1.22 min (Method RH B).

Stage 2: tert-butyl 2,2-dimethyl-4-(2-(3-sulfamoylpyrazol-1-yl)ethyl|pyrrolidine-1-carboxylate

I

(c) (c) ra and NA

Hv Osm 7 U nl U and OM -- from Mk

M-

And -

Potassium carbonate (1.264 g, 9.146 mmol), 1H-pyrazole-3-sulfonamide (449 mg, 3.051 mmol) and tert-butyl-2,2-dimethyl-4-(2-methylsulfonyloxyethyl)pyrrolidine solution were added to a 20 ml vial. -i-carboxylate (980 mg, 3.049 mmol) in M,M-dimethylformamide (12 mL). The reaction mixture was closed and placed in an oil bath at 75 "C and allowed to stir for 18 hours. The reaction mixture was quenched with brine and extracted with ethyl acetate 3 times. The organic layers were combined, dried over sodium sulfate,

filtered and evaporated. The reaction mixture was purified by column chromatography (0-3095 methanol in dichloromethane gradient) to give tert-butyl-2,2-dimethyl-4-(2-(3-sulfamoylpyrazol-1-yl)ethyl|pyrrolidine-1-carboxylate ( 259.0 mg, 23 95) as a white solid along with a smaller amount of regioisomeric byproduct. MO-IER t/2 calcd 372.18314, found 373.2 (M--1)k; retention time: 1, 39 min (Method RH B).

Stage 3: tert-butyl 4-(2-3-(2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl|pyrazole) -1-yl|ethyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-I3-IZ3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (271 mg, 0.6953 mmol), carbonyldiimidazole (136 mg, 0.8387 mmol) and tetrahydrofuran (3 ml). The reaction mixture was placed in an oil bath preheated to 357 and left to stir for 2 hours. The reaction mixture was then removed from the oil bath and solid tert-butyl-2,2-dimethyl-4-(2-(3-sulfamoylpyrazol-1-yl)ethyl|pyrrolidine-i-carboxylate (259 mg, 0.953 mmol) was added from the flask. , which was washed with tetrahydrofuran (2 mL), was added to the reaction mixture. 1,8-diazabicyclo(|5.4.Fzundec-7-ene (350 μL, 2.340 mmol) was added, and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched saline solution and extracted with ethyl acetate.

The organic layer was dried over sodium sulfate, filtered and evaporated to give a foam.

The foamy residue was purified by chromatography on silica gel (0 95-20 95 methanol in a dichloromethane gradient), obtaining tert-butyl 4-(2-3-(2-chloro-6-I(3-I3-(11-(trifluoromethyl)cyclopropyl) propoxy|pyrazol-1-yl|pyridine-3-carbonyl|Isulfamoyl|pyrazol-1-yl|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (336 mg, 65 95) as a white foam. TN NMR (400

MHz, DMSOSO-ab) 5 8.35 (y, U - 2.8 Hz, 1H), 8.08 (a, 9 - 8.2 Hu, 1H), 7.79 (5, 1H), 7.62 (y, U - 8.3 Hz, 1H), 6.59 (5, 1H), 6.13 (a, U - 2.8 Hz, 1H), 4.22 (1,9U -6.2 Hz, 2H), 4.13 (I, 9 - 7.2 Hz, 2H), 3.54 (a, U 2 23.2 . (yes, 9 - 18.7, 10.1 Hz, 1ЗН), 1.18 (а, У - 1.7 Hz, ЗН), 0.95 - 0.88 (t, 2Н), 0.79 - 0.72 (t, 2Н). MO-IER t/ calc. 743.248, found 744.4 (M--1) k; retention time: 1.81 min. (Method РХ 0).

Stage 4: 2-chloroN-(11-(2-(5,5-dimethylpyrrolidin-3-yl)ethyl|-1H-pyrazol-3-yl)usulfonyl)-6-(3-(3-

P-"trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)/upyridin-3-carboxamide (9) (9)

Sun Sun A r t96yu -

I am hundred at 4 o'clock

Gee! dm M SI shk Ge) dm M SI MM

Coo)

Tert-butyl 4-(2-IZ3-Ce-chloro-6-I13-I9-(11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl)|sulfamoyl|pyrazole- 1-yl|ethyl|-2,2-dimethylpyrrolidine-1-carboxylate (330 mg, 0.4434 mmol) and dichloromethane (b ml).

Trifluoroacetic acid (1.5 mL, 19.7 mmol) was added and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was evaporated to dryness, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (poor solubility in ethyl acetate). The organic layer was dried over sodium sulfate and filtered.

Most of the desired material was still on the filter cake, so the filter cake (mainly sodium sulfate) was dissolved in water and washed with additional ethyl acetate. The organic phase was separated and evaporated without drying over sodium sulfate.

The product was dried under vacuum to remove residual water before obtaining 2-chloro-N-(11-(2-(5,5-dimethylpyrrolidin-3-yl)ethyl|-1!H-pyrazol-3-yl)usulfonyl)-6 -(3-13-(11-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)upyridin-3-carboxamide (246 mg, 86 95) as a white solid. MO-IER t/2 calc. 643.19556, found 644.3 (M--1)k; retention time: 1.52 min. (Method of RH B).

Stage 5: 19,19-dimethyl-4-(3(13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21 -pentaazatetracyclo|15.2.1.111,14.02,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (Compound 273) (0) with kove | . m p ev ya uva U o u M si Shk o Mem se Mem -O r U

Molecular sieves Z A, potassium carbonate (264 mg, 1.910 mmol), cesium fluoride (116 mg, 0.7636 mmol) and a solution of 2-chloro-M-(11-(2-(5.5 -dimethylpyrrolidine-3-yl)ethyl|-1H-pyrazol-3-yl)usulfonyl)-6-(3-13-P1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)upyridin-3 -carboxamide (246 mg, 0.3819 mmol) in dimethyl sulfoxide (15 mL). The reaction mixture was closed and placed in an oil bath preheated to 150 C and left to stir overnight. The reaction mixture was allowed to cool to room temperature, filtered and purified by reversed-phase HPLC (10-99 95 acetonitrile in water with a modifier of 0.1 90 hydrochloric acid), obtaining 19,19-dimethyl-4-(3-13-(1- (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21- pentaazatetracycloi|15.2.1.111,14.02,7|genicose-2,4,6, 11(21),12-pentane-8,10,10-trione (compound 273) (25.5 mg, 11 95). MO-IER t/2 calc. 607.2189, found 608.3 (M.-1) same; retention time: 2.08 min. (Method of RH B).

Example 188: Preparation of 21,21-dimethyl-4-(3-13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14,23 -pentaazatetracycloi|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (Compound 275) ох / о х бо,

X 2 | Es i o hu on Ko; zir 1 oh gu zier2

M | 2 I Vosm M - i K m M si oo o- TM M si still va i es Y in all Gu Ou /v xx t Z m | them U vier Z m soto

M - Meooyannnnn yo | N o- TM M si mm ME M M--ki

Stage 1: tert-butyl 4-I(4-3-(2-chloro-6-I(3-I3-11-(trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|Ipyridine-3-carbonyl|Isulfamoyl| pyrazol-1-yl|brutyl|-2,2-dimethyl-pyrrolidine-1 ochre

Z ve 9 nm U ge GI oh r 5 M hu M ia. Z-475

VosM - o- TM M si o- MM M si

2-Chloro-6-I3-IZ3-P1-(trifluoromethyl)cyclopropyl|Ipropoxy|pyrazol-1-yl|pyridine-3-carboxylic acid (280 mg, 0.7184 mmol), carbonyldiimidazole (140 mg, 0.8634 mmol) and tetrahydrofuran (3 ml). The reaction mixture was heated at 35 "C for 90 min. The reaction mixture was removed from the oil bath and a solution of tert-butyl-2,2-dimethyl-4-|4-(3-sulfamoylpyrazol-y-yl) butylpyrrolidine-y-carboxylate ( 288 mg, 0.7190 mmol) in tetrahydrofuran (3 mL), followed by 1,8-diazabicyclo[(5.4.0)undec-7-ene (350 µL, 2.340 mmol).

The reaction mixture was allowed to stir for 18 hours, and then quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give a foam. The residual foam was purified by chromatography on silica gel (0 95-20 95 methanol in dichloromethane), obtaining tert-butyl 4-(4-(3-((2-chloro-6-I(3-(3-(1- (trifluoromethyl) cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|Isulfamoyl|pyrazol-1-vo2 yl|Ibsutyl|-2,2-dimethylpyrrolidine-1-carboxylate (159.1 mg, 29 95) as a white foam TN NMR (400

MgGu, DMOO-ab) b 12.88 (5, 1H), 8.39 (y, Y - 2.9 Hz, 1H), 8.08 (a, Y - 8.4 Hz, 1H), 8.00 (y, Y - 2.4 Hz, 1H), 7.69 (y, y - 8.3 Hz, 1H), 6.86 (y, y - 2.3 Hz, 1H), 6.19 (y, y - 2.9 Hz, 1H), 4.23, y - 6.3 Hz, 4H), 3.49 (d, U - 10.1 Hu, 1H), 2.73 (a, U - 10.0 Hu, 1H), 2.07 - 1.94 (t, 1H), 1.82 (aa, U - 27.6, 14.2, 7.0

Hu, 5H), 1.74 - 1.69 (t, 2H), 1.36 (a, U - 10.9 Hu, TON), 1.30 (a, U - 11.7 Hu, 5H), 1.18 (5, 4H), 0.95 - 0.87 (t , 2H), 0.80 - 0.70 (t, 2H). MO-IER t/2 calc. 771.27924, found 772.4 (Ma1)k; retention time: 1.99 min. (Method RK 5).

Stage 2: 2-chloroN-(11-(4-(5,5-dimethylpyrrolidin-3-yl)butyl|-1H-pyrazol-3-yl)usulfonyl)-6-(3(3-

P-"(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)/upyridin-3-carboxamide c) ес ох и оо хх м? x ES Tei n U z y: m U o y My si Shk M. - M--m tA chi shchi di

In a flask containing tert-butyl-4-I4-I3-(2g-chloro-6-I3-IT3-11- (trifluoromethyl)cyclopropyl|propoxy|pyrazol-1-yl|pyridine-3-carbonyl|sulfamoyl)| Dichloromethane (6 mL) and trifluoroacetic acid (600 μL, 7.788 mmol) were added to pyrazol-1-yl|Rutil|-2,2-dimethylpyrrolidine-1-carboxylate (156 mg, 0.2020 mmol). The reaction was left under stirring at room temperature for 1 hour. The reaction mixture was evaporated to dryness and saturated sodium bicarbonate solution was added until the pH of the reaction mixture reached 7. Ethyl acetate was added and the mixture was stirred for 3 minutes. The mixture was separated and the organic layer (incompletely dissolved) was evaporated to dryness and dried in vacuo overnight to give 2-chloro-N-(C1-4-(5,5-dimethylpyrrolidin-3-yl)butyl|-1H-pyrazole -3-yl)sulfonyl)-6-(3-13-11-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)pyridin-3-carboxamide (133 mg, 98 95) as a white solid . MO-IER t/: calc. 671.2268, found 672.4 (M--1)k; retention time: 1.56 min. (method RH b).

Stage 3: 21,21-dimethyl-4-(3(13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 23 -pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (Compound 275) and o (9, (0, es Z o o z s m? h es, rea

N | be M h a, a Jew; m M - - 75

Potassium carbonate (137 mg, 0.9913 mmol), cesium fluoride (62 mg, 0.4082 mmol), molecular sieves Z A and a solution of 2-chloro-M-((1-I(4-(5, 5-dimethylpyrrolidin-3-yl)butyl|-1H-pyrazol-3-yl)sulfonyl)-6-(3-13-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-

Z ylupyridine-3-carboxamide (133 mg, 0.1979 mmol) in dimethylsulfoxide (8 mL). The reaction mixture was placed in an oil bath preheated to 150 °C and allowed to stir for 18 hours. The reaction mixture was filtered and purified by reversed-phase HPLC (30-99 95 acetonitrile in water with 0.1 96 hydrochloric acid modifier), obtaining 21.21 -dimethyl- 4-(3-13-1-"trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14,23- pentaazatetracyclo!|17.2.1.111 ,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (compound 275) (58.6 mg, 47 95) as a white solid. MO- IER t/72 calcd 635.2502, found 636.4 (M--1) k, retention time: 2.22 min (Method RH B).

Example 189: Preparation of 21,21-dimethyl-4-(3-13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14,23 -pentaazatetracycloi|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) (Compound 276) and 21,21-dimethyl- 4-(3-73-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,23- pentaazatetracycloyl17.2.1.111, 14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 277) 6оЗ c) езс, и

Shk -i- in | H V, 5ier 1 c) (c) ko v es, i r sh- kv VO; square meter; epapioteg 1 epapioteg2

Stage 1: 21,21-dimethyl-4-(3 13-11-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14, 23- pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1 ) (Compound 2176) and 21,21-dimethyl- 4-(3-(3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,23- pentaazatetracyclo!|17.2.1.111, 14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 2) (Compound 277) c) o a xx -Ж y | N V 5ier 1 c) (c) gas y sy ry r r rev yashro ke VO; epapioteg 1 epapioteg2

Racemic //- 21,21-dimethyl-4-(3-73-(1-«"«trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9, 14 23-pentaazatetracyclo!|17.2.1.111,14.02,7|tricose-2,4,6,11(23),12-pentane-8,10,10-trione (53 mg, 0.08337 mmol) was separated using of chiral NCR using

SpigaI!Rak A5-H (column 250 x 21.2 mm, particle size 5 μm) with 25 95 acetonitrile:methanol (90:10; 20 MM MNH))/75 95 mobile phase of carbon dioxide at 10 ml/min with obtaining as the first eluted enantiomer, 21,21-dimethyl-4-(3-(3-(1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3 ,9,14,23- pentaazatetracyclo!y17.2.1.111,14,02,7|gricose-2,4,6,11(23),12-pentane-8,10,10-trione (enantiomer 1) ( compound 276) (19.6 mg, 74 do); IN NMR (400 MHz, DMSOO-ab) 5 12.57 (5, 1H), 8.20 (a, U - 2.8 Hz, 1H), 7.98 (5, 1H), 7.75 (5, 1H), 6.89 (y, U - 9.1 Hz, 2H), 6.11 (a, U - 2.3 Hz, 1H), 4.27 (5, 2H), 4.20 (1, 9 - 6.2 Hz, 2H), 2.72 (a, U - 9.3 Hu, 2H), 2.54 (5, 6H), 1.85 (ai, U - 10.3, 5.4 Hu, ZN), 1.75 - 1.69 (t, 2H), 1.61 (5, 4H), 1.52 (5, 4H), 0.93 - 0.89 (t, 2H), 0.77 - 0.73 (t, 2H), MO-IER t/2 calcd. 635.2502, found 636.4 (M'-1)g; Retention time: 2.24 min. (Method LC B) The second eluted enantiomer 21,21-dimethyl-4-(3-13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazole-1- il)- 10X6-thia-1,3,9,14, 23-pentaazatetracyclo!|17.2.1.111,14.02,7|gricose-2,4,6,11(23),12-pentane-8,10,10 -trione (enantiomer 2) (Compound 277) (16.6 mg, 63 90). MO-IER t/2 calc. 635.2502, found 636.4 (M--1) k; retention time: 2.22 min. (Method of RH B).

Example 190: Preparation of 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3, 9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (atropoisomer 2, enantiomer 1) (Compound 285 ) and 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10AX6-thia-1,3,9 ,13,14-

pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 2, enantiomer 2) (Compound 286) (c) all and : Max

N Y 5ier1 gasetis aigorizoteg 2 (in) o oh (o) (in) i i r: xx

M - I

Y Y aigorizoteg 2, epapioteg 2 aigorizoteg 2, epapioteg 1

Stage 1: 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-5 10X6-thia-1,3, 9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 2, enantiomer 1) (Compound 285 ) and 20,20,22-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3,9 ,13,14- pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (atropoisomer 2, enantiomer 2) (Compound 286) (c) 5 all and: mach

N Y 5ier1 gasetis aigorizoteg 2 (c)

Ge) Оу / (o) (c) и

F Z oh -/ M - She

Y Y aigorizoteg 2, epapioteg 2 aigorizoteg 2, epapioteg 1 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1 H-pyrazol-1-yl|- 10X6-thia-1,3,9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione (17 mg, 0.02788 mmol) (racemic atropoisomer 2) was separated by chiral NCR using a SpigaiRak AZ-N (column 250 x 10 mm, particle size 5 μm) with a mobile phase of 24 9o acetonitrile:methanol (90:10; 20 mM MNH ))/76 95 carbon dioxide at 10 ml/min, which gives the first eluted enantiomer, 20,20,22-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole -1-yl|-10X6-thia-1,3,9,13,14-pentaazatetracycloi!16.2.1.111,14.02,7|docosa- 2,4,6,11(22),12-pentane-8,10 ,10-trione (atropoisomer 2, enantiomer 1) (Compound 285) (5.4 mg, 64 95) as a yellow solid. 1H NMR (400 MHz, DMSO-ab) 612.16 (p5, 1H), 8.19 (a, 9-28

Gu, 1), 7.81 (a, 9U-7.9 Hz, 1H), 7.71 (5, 1H), 6.92 (a, 9-7.9 Hz, 1H), 6.10 (a, 9U-2.8 Hz, 1H), 4.35 ( t, 1H), 4.22 (p5, 2H), 4.02 (t, 1H), 2.66 (5, ЗН), 2.39 (t, 1Н), 2.02 (t, ЗН), 1.83 (t, 2Н), 1.65 (aa , 912.1 Hz, 5.6 Hz, 1H), 1.50 (d, U-15.6 Hz, 12.4 Hz, 2 H), 1.50 (t, 8H), 1.36 (d, 9U-15.6 Hz, 12.4 Hz, 2H), 1.22 ( 5, 6H), 1.12 (t, 1H). MO-IER t/2 calc. 609.2345, found 610.4 (Ma1)k; retention time: 3.14 min. (Method РХ 0). The second eluted enantiomer was 20,20,22-trimethyl-4-

IZ-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7 |docose-2,4,6,11(22),12-pentane-8,10,10-trione

(atropoisomer 2, enantiomer 2) (Compound 286) (6.5 mg, 76 95), isolated as a yellow foam.

MO-ER t/2 calc. 609.2345, found 610.4 (M--1)k; retention time: 3.14 min. (Method РХ 0).

Example 191: Preparation of 12,20,20-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1,3, 9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (enantiomer 1) (Compound 290) and 12 ,20,20-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 291)

Stage 1: 12,20,20-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9 ,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 1) (Compound 290) and 12, 20,20-trimethyl-4-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9,13,14- pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 291) and "zh | - . m I -/ hau lu Mi DA lu m da

Racemic 12,20,20-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9,13 ,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (73 mg, 0.1197 mmol) was subjected to chiral NKR- chromatography using

SpigaI!Rak A5-H (column 250 x 21.2 mm, particle size 5 μm) with 20 95 acetonitrile:methanol (90:10, 20 mM MNH))/80 95 mobile phase of carbon dioxide at 70 ml/min, giving as the first enantiomer for the eluate, 12,20,20-trimethyl-4-|3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10A6-thia-1 ,3,9,13,14-pentaazatetracyclo|16.2.1.111,14.02,7|docose-2,4,6,11(22),12- pentane-8,10,10-trione (enantiomer 1) (Compound 290 ) (35.1 mg, 92 to). MSO-IER t/:2 calc. 6092345, found 610.4 (Mya1)-4; Holding time: 3.07 min. (Method РХ 0). The second eluted enantiomer was 12,20,20-trimethyl-4-I3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl|-10X6-thia-1,3,9 ,13,14-pentaazatetracycloi|16.2.1.111,14.02,7|docose-2,4,6,11(22),12-pentane-8,10,10-trione (enantiomer 2) (Compound 291) (28, 5 mg, 78 95). IN NMR (400 MHz, DMSOSO-ab) 612.16 (65, 1H), 8.38 (5, 1H), 8.19 (0, U - 2.8 Hz, 1H), 7.81 (a, 9 - 7.9 Hu, 1H), 6.92 ( a, U - 7.9 Gu, 1H), 6.10

Zo (9.9 - 2.8 Gu, 1H), 4.35 (t, 1H), 4.22 (p5, 2H), 4.02 (t, 1H), 2.38 (5, ЗН), 2.02 (t, ЗН), 1.83 (t . 5, 6H), 1.12 (t, 1H). MO-IER t/2 calc. 609.2345, found 610.4 (M--1)k; retention time: 3.07 min. (Method РХ 0).

Example 192: Preparation of 5,5-dimethyl-9-(3-(2-/1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15A6bthia-2,6,8,14,20 -pentaazatetracyclo|14.3.1.13,6.07,12|genicose-1(20),7,9,11,16,18-hexane-13,15,15-trione (compound 31)

Hey guys, what's wrong with M and what. take M ak Vivr Z M och vera " 9 і ж у о и | и о о о о о о

Mcheny" x OB nn | with berb nat I and She. soy with zhk (o; -- tt o X v chi

I'm a lot

GI o o

WITH

By o 5 m 5

V I Vier8 o photo M M

As M s Mykh eV Mn - d- chn s NM ghne Hu

Stage 1: 1-benzyl-5,5-dimethylpyrrolidin-3-one (c) (c)

M

JSC (-

To a stirred solution of 5,5-dimethylpyrrolidin-3-one (1.020 g, 9.014 mmol) in anhydrous acetonitrile (30 mL) was added anhydrous potassium carbonate (5.00 g, 36.18 mmol) under nitrogen at ambient temperature. After stirring for 15 minutes, benzyl bromide (1.2 mL, 10.09 mmol) was added. After 7 h, the reaction mixture was filtered and the filtrate was concentrated by mass to obtain a crude product, which was extracted from water (20 ml) with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with water and dried over anhydrous sodium sulfate, filtered through a pad of silica gel, and concentrated in vacuo to give the crude product, 1-benzyl-5,5-dimethylpyrrolidin-33-one (1.67 g, 91 95) in in the form of an orange viscous material, which was used in the next reaction without additional purification. MO-IER t/72 calc. 203.13101, found 204.1 (Ma-1)zh-; retention time: 0.81 min. (Method of RH B).

Step 2: (E)-M-(1-benzyl-5,5-dimethylpyrrolidin-3-ylidene)-2-methylpropane-2-sulfinamide.

She d-

M. o

M ra: M Ov i nl -- II (c)

To a stirred solution of 1-benzyl-5,5-dimethylpyrrolidin-3-one (1.762 g, 8.668 mmol) and 2-methylpropane-2-sulfinamide (1.157 g, 9.546 mmol) in anhydrous tetrahydrofuran (70 mL) was added titanium ethoxide (IM ) (7.3 mL, 34.82 mmol) under a nitrogen atmosphere at ambient temperature. The reaction mixture was allowed to stir at 80 "C for 13 hours, then allowed to cool to ambient temperature. The reaction was slowly quenched with saturated aqueous sodium bicarbonate until some precipitate formed (although titanium salts are white, the color of the product made the salt appear brown) (about 40 mL of sodium bicarbonate was used). The inorganic suspension was filtered through a pad of celite and the filter cake was washed with ethyl acetate (100 mL). After the layers were separated from the filtrate, the aqueous portion was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed saline solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (E)-M-(1-benzyl-5,5-dimethylpyrrolidin-3-ylidene)-2-methylpropan-2-sulfinamide (2.602 g, 98 95) in the form of a brown solid, which was used in the next reaction without further purification. MSO-IER t/72 calcd. 306.17657, found 307.2 (MA) k; retention time: 0.8 min. (С manual RK B).

Stage 3: M-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)-2-methylpropane-2-sulfinamide d-x

M M that

Her - oy -- HER o o)

To a stirred solution of (E)-M-(1-benzyl-5,5-dimethylpyrrolidin-3-ylidene)-2-methylpropane-2-sulfinamide (770 mg, 2.51 mmol) in anhydrous methanol (3 mL) and tetrahydrofuran (10 ml) at -10 "C was added sodium borohydride (290 mg, 7.665 mmol) in three portions under a nitrogen atmosphere. The reaction mixture was allowed to warm to 0 "C and stirred at this temperature for 2 hours. The reaction was quenched with aqueous MNACl (5 mL) and then with saturated aqueous sodium bicarbonate (20 mL). The volatiles were removed and the remaining aqueous portion was extracted with ethyl acetate (25 mL). The aqueous layer was additionally extracted with ethyl acetate (2 x 15 ml). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give crude M -(1-benzyl-5,5-dimethylpyrrolidin-3-yl)-2-methylpropane-2-sulfinamide (650 mg, 8495) as brown solid. MO-IER t/2 calc. 308.19223, found 309.2 (Ma-1)f; retention time: 0.63 min. (Method of RH B).

Stage 4: 1-benzyl-5,5-dimethylpyrrolidine-3-amine (dihydrochloride salt)

N

M

MN that (5. (c) gne

Crude M -(1-benzyl-5,5-dimethyl-pyrrolidin-3-yl)-2-methylpropane-2-sulfinamide (650 mg, 2.107 mmol) was dissolved in methanol (10 mL) and hydrogen chloride (2.2 mL) 4.0 M in dioxane, 8.800 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 hour.

Volatile substances were removed under reduced pressure. Trituration with ether was attempted, but the crude product turned to a sticky material, so the ether was removed under reduced pressure and the resulting material was dried in vacuo to give 1-benzyl-5,5-dimethylpyrrolidine-3-amine (dihydrochloride salt ). (580 mg, 9995) in the form of a brown resinous mass. Mine was used in the next reaction without further purification. MO-IER n/2 calc. 204.16264, found 205.1 (M'-1) w; retention time: 0.3 min. (Way

RK B).

Stage 5: 6-K1-benzyl-5,5-dimethylpyrrolidin-3-ylamino|Ipyridine-2-sulfonamide o o o, I

Mn, I NA hu h yan M: -- 2 | M u

M 2

MN

NOI E

A 20 mL vial was charged with b-fluoropyridine-2-sulfonamide (0.351 g, 1.992 mmol) and anhydrous dimethyl sulfoxide (5 mL), followed by the addition of anhydrous potassium carbonate (1.377 g, 9.963 mmol) and 1-benzyl-5,5-dimethylpyrrolidine. -3-amine (dihydrochloride salt) (0.580 g, 2.092 mmol), in the indicated order. The vessel was sealed under a nitrogen atmosphere and forced to 70C in an oil bath for 13 hours, then at 90C for 8 hours followed by brief heating at 100C for about 30 minutes. The reaction mixture was filtered through a pad of Celite, then diluted with ethyl acetate (30 mL) and neutralized with ice-cold ASON to pH - 7. Washed with water (15 ml), and then with saline solution (15 ml).

The organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure.

The crude substance was purified by silica gel chromatography. Initially, the use of a gradient from 2095 to 100 95 ethyl acetate in hexane did not give pure product. A second purification by silica gel chromatography (0-15 95 methanol in dichloromethane) afforded the desired compound, 6-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)amino|Ipyridine-2-sulfonamide (125 mg, 17 95 ) in the form of a light brown solid. MOS-IER t/72 calc. 360.162, found 361.2 (Ma1)k; retention time: 0.59 min. (Method of RH B).

Stage 6: 6-(5,5-dimethylpyrrolidin-3-ylamino|pyridine-2-sulfonamide)

M M

---yeah

Mu yah M ih

MN MN

A stirred solution of 6-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)amino|pyridine-2-sulfonamide (125 mg, 0.3468 mmol) in anhydrous methanol (8 mL) was treated with palladium on charcoal (40 mg, 0.03759 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at 52 C in a hydrogen atmosphere (balloon) for 10 hours. The reaction mixture was allowed to cool to ambient temperature, air was evacuated from the flask, nitrogen was filled, then palladium hydroxide (25 mg, 0.03560 mmol) was added. Again, the reaction mixture was stirred at 52 "C in a hydrogen atmosphere (balloon) for 7 hours, then allowed to cool to ambient temperature. The catalyst was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain 6-(5.5 -dimethylpyrrolidine-

C-yl)amino|Ipyridine-2-sulfonamide (61 mg, 65 Fo) as a light brown solid, which was used in the next reaction without further purification. MO-IER t/: calc. 270.11505, found 271.1 (Ma-1) same; retention time: 0.53 min. (Method of RH B).

Stage (7:00 2-chloro-M-(6-(5,5-dimethylpyrrolidin-3-yl)amino|-2-pyridyl|isulfonyl|-6-(3-(2-11- (trifluoromethyl)cyclopropyl| ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) o Gi (o) (c) r ek on | y Y | y na | 5 | Mo. r Mych

Mt, o dm Ks si not FI M si va 5-7 - NM Also vd - her 6-K5,5-dimethylpyrrolidin-3-ylamino|Ipyridine-2-sulfonamide (43 mg, 0.1591 mmol) and carbonyldiimidazole ( 29 mg, 0.1788 mmol) were combined in dry tetrahydrofuran (3 ml) and stirred under nitrogen at 48 "С for 1 h. Then a solution of 2-chloro-6-|3-(2-(1- (trifluoromethyl )cyclopropyl|ethoxy|pyrazol-1-yl|Ipyridine-3-carboxylic acid (60 mg, 0.1597 mmol) in dry tetrahydrofuran (1 mL), followed by 1,8-diazabicyclo/5.4.F)undec-7- en (30 μl,

From 0.2006 mmol). The reaction mixture was removed from the heat and stirred at ambient temperature for 12 hours. Volatiles were removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1.5 mL), filtered through a 0.45 μm UmMpaytap syringe disk filter, and purified by preparative reversed-phase HPLC (1-99 95 acetonitrile in water, hydrochloric acid as modifier) with the formation of 2-chloro-M-I|(6- (5,5-dimethylpyrrolidin-3-yl)amino|-2-pyridyl|sulfonyl|-6-(3-(2-(1- (trifluoromethyl) cyclopropyl|ethoxy|pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) (13 mg, 12 95) as an off-white solid 1H NMR (400 MHz, DMSOSO-ab) b 9.09 (5, 2H ), 8.40 (a, - 2.9 Gu, 1H), 8.13 (a, 9 - 8.3 Hz, 1H), 7.77 - 7.63 (t, ЗН), 7.23 (j, 9) - 7.2 Hz, 1H), 6.81 (a , U - 8.4 Hz, 1H), 6.18 (y, U - 2.9 Gu, 1H), 4.45 - 4.36 (t, 1H), 4.34 (1, 9 - 7.1 Hz, 2H), 3.72 - 3.62 (t, 1H) , 3.26 - 3.14 (t, 1H), 2.24 (da, U - 13.4, 8.3 Hz, 1H), 2.08 (I, U - 7.1 Hz, 2H), 1.89 (aa, U -

14.4.0 Hz, 1H), 1.48 (5, ЗН), 1.28 (5, ЗН), 1.00 - 0.92 (t, 2Н), 0.94 - 0.85 (t, 2Н). MO-IER t/2 calc. 627.16425, found 628.2 (M--1)k; Holding time: 1.55 min. (Method of RH B).

Stage 8: 5,5-dimethyl-9-(3-2-|1-trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15A6thia-2,6,8,14,20- pentaazatetracyclo/14.3.1.13,6.07,12|genicose-1(20),7,9,11,16,18-hexane-13,15,15-trione (compound 31) those (c) (c)

Is it 5 m wide? xx | 7 and | and:

N | M. 8 M ikh

M and Mach o- M M

In M. si st 7. xx

Mn ppt--- MN ko) 5-7 NM hne Hu

To a solution of 2-chloro-M-(6-(5,5-dimethylpyrrolidin-3-yl)amino|-2-pyridyl|sulfonyl|-6-(3-(2-11- (trifluoromethyl)cyclopropyl|ethoxy|pyrazole) -1-yl|Ipyridine-3-carboxamide (dihydrochloride salt) (11 mg, 0.01569 mmol) in anhydrous dimethyl sulfoxide (1.5 mL), cesium fluoride (3 mg, 0.01975 mmol), potassium carbonate (12 mg, 0.08683 mmol) (ground in a mortar and pestle) and a small amount of granular 4 A molecular sieves (about 500 mg heated with a heat gun for 5 minutes to dryness). The resulting mixture was sealed under nitrogen and heated at 150C for 17 hours, then allowed to cool to ambient temperature, allowing the solid to settle to the bottom. The supernatant was filtered through a 0.45 µm PTFE UU Pipetpap syringe disc filter. The filtrate was concentrated and purified using reversed-phase HPLC-MS using a GI ipa C column 18 (2) and a double gradient from 1 95 to 99 95 acetonitrile in water (without modifier), obtaining 5,5-dimethyl- 9-(3-(2-(/1-(trifluoromethyl)cyclopropyl|ethoxy)-1H-pyrazol-1-yl)-15A6-thia-2,6,8,14,20-pentaazatetracyclo/|14.3.1.13 ,6.07,12|genicose-1(20),7,9,11,16,18-hexane-13,15,15-trione (compound 31) (3.5 mg, 3790). MO-IER t/72 calc. 591.18756, found 592.3 (M--1)k; retention time: 1.6 min. (Method of RH B).

Example 193: Preparation of (145)-12,12-dimethyl-8-(3-oxo-octahydroimidazo|1,5-a|pyridin-2-yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 213) o o TI 6) ( c) o, / X s re 0 m och M MN vir 1 o | And | and and | Zh with Zh, X - M. i

I WHAT M M M

MN

MN

Stage 1: (145)-12,12-dimethyl-8-(3-oxo-octahydroimidazo|(1,5-a|pyridin-2-yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(23),5(10),6,8,19,21-hexane-2,2,4-trione (Compound 213) (c) (c) o, lo u chva chasvihe; M t xx I ra s -- - -' XX M okho 4

MN

MN

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10|hetracose-1( 23),5,7,9,19,21-hexane-2,2,4-trione (100 mg, 0.2222 mmol), 2,5,6,7,8,va-hexahydro-1H-imidazo( 1,5-a|Ipyridine-Z3-one (45 mg, 0.3210 mmol),

Rag(aura)z (54 mg, 0.05897 mmol), xanthophos (33 mg, 0.05703 mmol), cesium carbonate (375 mg, 1.151 mmol), and anhydrous dioxane (1.6 mL). The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120 "С for 20 h, and then cooled to room temperature. The solvent was evaporated and the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by reverse-phase preparative chromatography using column C18 (10 95-99 96 acetonitrile in water - 5 mM hydrochloric acid).

The product fractions were combined, saline solution was added and organic solvents were evaporated.

The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered, and evaporation of the solvents gave a solid. The resulting solid was purified by chromatography on silica gel using a gradient of 100 96 dichloromethane to 596 methanol in dichloromethane to give (145)-12,12-dimethyl-8-(3-oxooctahydroimidazo|1,5- a|pyridin-2-yl) -2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|tetracose-1(23),5(10),6,8,19,21- hexane-2, 2,4-trione (compound 213) (58.6 mg, 47 95). 1H NMR (400 MHz,

SNiogoitogt-a) b 10.77 (5, 1H), 8.01 (a, U - 8.7 Hz, 1H), 7.90 (a, U - 8.7 Hz, 1H), 7.61 - 7.49 (t, 2H), 6.54 (r, U - 3.7 Hz, 1H), 4.79 (a, U - 7.9 Hz, 1H), 4.21 - 4.07 (t, 1H), 4.02 (aa, U - 12.5, 3.6 Hu, 1H), 3.83 (5, 1H), 3.64 - 3.48 (t, 2H), 3.32 (Yi, U - 8.9 Hu, 1H), 3.15 (y, U - 14.0 Hu, 1H), 3.04 (y, U - 9.4 Hu, 1H), 2.83 - 2.74 (t, 1H), 2.11 (yes, U - 12.4, 8.6 Hz, 1H), 2.00 - 1.85 (t, 2H), 1.71 (a, U - 9.8 Hz, 2H), 1.57 (a, U - 2.0 Hz, 6H), 1.55 (9, U - 1.2 Gu, ZN), 1.51 - 1.43 (t, ZN), 1.37 (I, U - 12.8 Hz, 2H). MO-IER t/2 calc. 553.24713, found 554.2 (M--1) k; Holding time: 1.62 min. (Method of RH E).

Example 194: Preparation of (145)-12,12-dimethyl-8-11-oxo-2-azaspiro|4.5|decan-2-yl)-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!| 17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,A4-trione (Compound 222) (9) (9) o o o Ry

Bucha o d 8 sia sha sh i t

N | Y kN Zer 1 k SCHO

SI in M M-- and M M

MN MN

Stage 1: (145)-12,12-dimethyl-8-11-oxo-2-azaspiro|4.5|decan-2-yl)-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 222) (9)

O o o Our re 8 o d 8 xx 2 7 se o | N m | y I ry SK Sh yo M M

SI M M

(145)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose was loaded into a 5 ml ampoule 1(23),5,7,9,19,21-hexane-2,2,4-trione, (50 mg, 0.1111 mmol), 2-azaspiroI(4,5|decan-1-one (24 mg, 0.1566 mmol), Rag(ara)3 (26 mg, 0.02839 mmol), xanthophos (16 mg, 0.02765 mmol), cesium carbonate (180 mg, 0.5525 mmol) and anhydrous dioxane (800 The mixture was purged with nitrogen for 1-2 min, closed with a lid and stirred at 120 "С for 20 h, and then cooled to room temperature. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), subjected to

From microfiltration and purified by reverse-phase preparative chromatography using a C18 column (10 95-99 96 acetonitrile in water - 5 mM hydrochloric acid).

The product fractions were combined, saline solution was added and organic solvents were evaporated.

The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered, and evaporation of the solvents gave a solid. The crude material was then purified by chromatography on silica gel using a shallow gradient from 100 95 dichloromethane to 5595 methanol in dichloromethane. Pure fractions were collected and the solvents were evaporated, obtaining (145)-12,12-dimethyl-8-/1-oxo-2-azaspiro|4.5|decan-2-yl)-2Ab-thia-3 as an off-white solid ,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 222) (13.01 mg, 20 95 ). IN NMR (400 MHz, Spiogotogt-a) b 10.41 (5, 1H), 8.10 - 7.95 (t, 2H), 7.62 - 7.49 (t, 2H), 6.55 (aa, U - 6.8, 2.4 Hz, 1H), 4.74 (5, 1H), 3.93, 9 - 7.2 Hz, 2H), 3.90 - 3.79 (t, 1H), 3.32 (da, 9 - 10.0, 7.7 Hz, 1H), 3.16 (y, 9 - 14.3 Gu, 1H ), 3.07 (5, 1H), 2.68 (449, 9 - 11.9, 6.4 Hz, 1H), 2.11 (ai, 9 - 12.4, 8.4 Hz, 1H), 2.03 (da, U - 8.0, 6.3 Hz, 2H) . , 1H), 0.91 - 0.79 (t, 2H). MO-IER t/2 calc. 566.2675, found 567.2 (M.-1)w; Holding time: 2.01 min. (Method of RH E).

Example 195: Preparation of 8-I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05 ,10.011,15)hetracose-1(23),5,7,9,20(24),21-hexane-2,2,4-trione (Compound 232) (9)

Nm | te Vier1 t | M | eh Zer2 "t on ro x " SI My si M- s "m pom AD (9)

I would (in) va and Z Ge) and and oh

GT AK vaz t - M. Zh i M Mn M M M M M M

SI M M u u M o izh 7

Mn

Stage 1: 2,6-dichloro-M-|((6-I(3-(5,5-dimethylpyrrolidin-2-yl)/propylamino |-2- pyridyl|sulfonyl|pyridine-3-carboxamide (hydrogen chloride salt) (o) (c) o (o) (c) o rea te nm | y: y M kh nn y | on , ЧО ш k |

SI M SI what

SI M si Vos M MN NM MN

AD not in M

A 50 mL flask charged with 2,6-dichloropyridine-3-carboxylic acid (733 mg, 3.818 mmol) and carbonyldiimidazole (620 mg, 3.824 mmol) was evacuated/backfilled with nitrogen.

Tetrahydrofuran (15 mL) was added and the mixture was stirred at 50 °C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-5-I3-((b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine) was added - 1-carboxylate (1.5 g, 3.636 mmol) and 1,8-diazabicyclo/5.4.0undec-7-ene (41385 mg, 9.098 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred overnight at 50 "C for overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated by mass, then purified by preparative reversed-phase chromatography using a C18 column (5-95 95 acetonitrile in water) to give the intermediate acylsulfonamide. A solution of this intermediate compound in dioxane (5 mL) was treated with hydrochloric acid (b mL, 6 M in dioxane, 36.00 mmol) and stirred at room temperature for 3 h.The mixture was evaporated in vacuo to give 2,6-dichloro-M-|(6 -(3-(5,5-dimethylpyrrolidin-2-yl/upropylamino|-2-pyridyl|isulfonyl|pyridine-3-carboxamide (hydrochloride salt)) (0.9 g , 47 95). MSO-IER t/:2 calc. 485.10553, found 486.15 (M'-1); retention time: 0.42 min. (Method of RH A).

Stage 2: 8-chloro-12,12-dimethyl-2Abthia-3,9,11,19,24- pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20( 24) 21-hexane-2,2,4-trione o o 0,0 i C 2 | M | Eh with | t | and:

N still p - - : -yaz 2 -j-6 U M. -2 si M SI y SI M M

NM MN MN

- NSII in M

Potassium carbonate (133 mg, 0.9623 mmol), cesium fluoride (60 mg, 0.3950 mmol) and molecular sieves 4 A (300 mg) were hermetically closed in a 5 ml vial and purged with nitrogen. Then a solution of 2,6-dichloro-M-((6-(3-(5,5-dimethylpyrrolidin-2-yl)propylamino|-2-pyridyl|sulfonyl|pyridine-3Z-carboxamide (hydrochloride salt)) (100 mg, . /8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20( 24) 21-hexane-2,2,4-trione (20.8 mg, 24 95). MO-IER t/2 calculated 449.12885, found 450.18 (Ma1)g; retention time: 1.46 min. (Method RH B).

Stage C: 8-3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05, 10.011,15)hetracose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (Compound 232) (ti o (o (c) och r o ra - m : X "sha otr

Y Y Y Y ; МН in xx y

So, M. - --4 M. - si M m X / ZK yk M m M ov! I

Solution of 8-chloro-12,12-dimethyl-2Abthia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20(24) 21-hexane-2,2,4-trione (200 mg, 0.4445 mmol), 1-(3,3-dimethylbutyl)imidazolidinyl-2-one (114 mg, 0.6696 mmol), xanthophos (65 mg, 0.1123 mmol), Rag(ara)z (102 mg, 0.1114 mmol) and cesium carbonate (724 mg, 2.222 mmol) in dioxane (4 mL) were degassed by purging with nitrogen for 2 minutes. The mixture was stirred at 120 C overnight. The reaction mixture was filtered and purified by reverse-phase preparative HPLC (column C 18, 1-99 95 acetonitrile in water with a hydrochloric acid modifier) to obtain 8-I(3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl |-12,12-dimethyl-2Ab6-thia-3,9,11,19,24-pentaazatetracyclo|18.3.1.05,10.011,15)hetracose-1(23),5,7,9,20(24) 21 -hexane-2,2,4-trione (compound 232) (9 mg, C 90). MSO-IER t/2 calc. 583.29407, found 584.39 (M--1) k; retention time: 1.71 min. (Method of RH B).

Example 196: Preparation of 19,19-dimethyl-4-(3-13-/1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21 -pentaazatetracyclo|15.2.1.111,14.02,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (enantiomer 1) (Compound 279) and 19,19-dimethyl- 4-(3-73-11-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21- pentaazatetracyclo!|15.2.1.111,14.02, 7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (enantiomer 2) (Compound 278)

GT (o) (o) a 5-7 and zd (9) (9) o r zy - ih 4 t U

We; EV 5-0 land MM w 3.-4 M MM vl Es

And epapiyoteg 2 epapioteg 1

Stage 1: 19,19-dimethyl-4-(3-13-1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21- pentaazatetracyclo|15.2.1.111,14.02,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (enantiomer 1) (Compound 279) and 19,19-dimethyl-4 -(3-(3-(1- (trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21- pentaazatetracyclo!|15.2.1.111,14.02 ,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (enantiomer 2) (Compound 278)

we -Ж g (9) (9) o r h i m? x and M U

N | M and | и ТСИ вл

And epapiyoteg 2 epapioteg 1

Racemic 19,19-dimethyl-4-(3-13-11-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21-pentaazatetracyclo |15.2.1.111,14.02,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (21 mg, 0.03456 mmol) was subjected to chiral NKR chromatography using

SpigaIRak A5-H (column 250 x 21.2 mm, particle size 5 μm) with 25 95 acetonitrile:methanol (90:10, 20 mM MNH))/75 95 mobile phase of carbon dioxide at 10 ml/min, giving as of the first eluted enantiomer 19,19-dimethyl-4-(3-13-/1-(trifluoromethyl)cyclopropyl|propoxy)-1H-pyrazol-1-yl)-10A6-thia-1,3,9,14, 21-pentaazatetracycloi|15.2.1.111,14.02,7|genicose-2,4,6,11(21),12- pentane-8,10,10-trione (enantiomer 1) (compound 279) (7.3 mg, 70 90). IN NMR (400 MHz, DMSO-4ab) b 12.61 (5, 1H), 8.18 (a, 9 - 2.7 Hz, 1H), 8.01 (5, 1H), 7.65 (y, 9U - 8.2 Hz, 1H), 6.93 (c, 1H), 6.85 (y, 9 - 8.2 Hz, 1H), 6.09 (a, 9U - 2.7 Gu, 1H), 4.59 (a, U - 13.9 Hz, 1H), 4.23 - 4.08 (t, ЗН) . 1.65 (t,

ЗН), 1.56 (5, ЗН), 1.49 (5, 4Н), 0.95 - 0.88 (t, 2Н), 0.79 - 0.70 (t, 2Н). MO-IER t/2 calc. 607.2189, found 608.3 (M--1)f; Holding time: 2.08 min. (Method of RH B). The second eluted enantiomer 19,19-dimethyl-4-(3-13-P1-(trifluoromethyl)cyclopropyl|Ipropoxy)-1H-pyrazol-1-yl)-10X6-thia-1,3,9,14,21-pentaazatetracyclo |15.2.1.111,14.02,7|genicose-2,4,6,11(21),12-pentane-8,10,10-trione (enantiomer 2) (Compound 278) (7.8 mg, 7090). MO-IER t/72 calc. 607.2189, found 608.4 (M--1) k; retention time: 2.08 min. (Method of RH B).

Example 197: Preparation of (145)-8-I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2A6b-thia-3,9,11,18,23-pentaaztetracycloi |17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 128) (0) oh -o (in ) huh? zhi zu H o | waded

And | t M MN - same y - M si i her She ZK i eat m M their code; - hee and

Stage 1: (145)-8-I3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo! |17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 128) (0) oh -o (in ) in 7 Shchi and ; and AD x | In SHI and

No. Ma | M MN -- (5 years M m MI

(14 Z)-8-chloro-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracyclo!i17.3.1.111,14.05, 10|hetracose-1(23),5,7,9,19,21-hexane-2,2,4-trione (25 mg, 0.05373 mmol), 1-(3,3-dimethylbutyl)imidazolidinyl-2 -one (13 mg, 0.07636 mmol), Rag(ara)z (13 mg, 0.01420 mmol), xanthophos (8 mg, 0.01383 mmol), cesium carbonate (88 mg, 0.2701 mmol) and anhydrous dioxane (400 μl). The mixture was bubbled with nitrogen for 1-2 minutes, closed and stirred at 120 "C for 5-14 hours (heating failed during the 14-hour period at an unknown time). The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide

(900 μl), microfiltered and subjected to reversed-phase preparative HPLC (C18) using a gradient of acetonitrile in water (from 1 95 to 99 95) and hydrochloric acid as a modifier. HPLC preparative HPLC showed partial conversion to the expected product (about 20 95), which was collected and combined with the product of the second reaction described below.

The second reaction was carried out again with the same amount of reagents and stirred at 120 C for 19 hours. The solvent was evaporated, dimethyl sulfoxide (1 mL) was added, and the mixture was purified by preparative reversed-phase HPLC (C18) using a gradient of acetonitrile in water (from 1 95 to 99 95) and hydrochloric acid as a modifier. Pure fractions were combined with the fractions of the first experiment, a little salt solution was added, and organic solvents were evaporated. The product was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Filtration followed by evaporation of the solvents gives a solid.

The solid residue was purified by flash chromatography on silica using a gradient of methanol (from 0 95 to 5 95) in dichloromethane to give (145)-8-N3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl|- 12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-hexaene-2,2,4-trione (compound 128) (17 mg, 27 95) as an off-white solid. 1H NMR (400 MHz, DMSO-ab) b 12.29 (5, 1H), 7.62 - 7.52 (t, 2H), 7.41 (a, 9 - 8.6 Hz, 1H), 7.03 (a, U - 7.2 Hz, 1H) . 10.1, 6.1 Hu, 2H), 3.12 - 3.03 (t, 1H), 2.93 (0, U - 13.4 Hu, 1H), 2.76 - 2.62 (t, 1H), 2.08 (horn 5, 1H), 1.85 - 1.68 ( t, 2H), 1.64 - 1.34 (t, 11H), 1.36 - 1.25 (t, 1H), 0.92 (5, 9H). MO-IER t/: calc. 583.29407, found 584.4 (M.-1) k; retention time: 1.88 min. (Method of RH B).

Example 198: Preparation of (145)-8-(3,4-dihydro-2H-pyran-b-yl)-12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3 .1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 303) (o) (c) ra

KK yr AD ty (in) | M SI su)

SI M si (o) a KU M xx on no | and: | and and | y (c) - Y ee i vier Z y My si -y peri

M si TE | ----

Mn; AMN

M M

5-X 5-X -- o -- o (o) (o)

IM M xx m t y: y y: shchi | saw 5 o | ro Ii Z- (o) - M V- M M

M si

Cl

Mn

LEA x /

NM

Stage 1: tert-butyl 2-chloro-6-(3,4-dihydro-2H-pyran-b-yl/upyridin-3-carboxylate

(c) (c) ra

Y Z ze (c) v... y 5 o) -- yun --:D- -- o | p (c) | M SI -

SI M SI

Tert-butyl 2,6-dichloropyridine-3-carboxylate (10.09 g, 40.668 mmol), 2-(3,4-dihydro-2H-pyran-b-yl) was charged to a 50 ml round-bottom flask equipped with a magnetic stirrer )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.55 g, 49.215 mmol) and Ra (PPRIZ) 2СИ2 (1.42 g, 2.0231 mmol) in

EN (10 ml), toluene (10 ml) and water (2 ml). The mixture was refluxed at 95°C overnight in an oil bath. The cooled reaction mixture was concentrated, then dissolved in ethyl acetate and washed with aqueous brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain a crude oil, which was purified by silica gel chromatography. , using a gradient of 100 95 hexanes to 5 95 ethyl acetate in hexane to give tert-butyl 2-chloro-6-(3,4-dihydro-2H-pyran-b-yl/upyridin-3-carboxylate (9.2 g, 76 95) in the form of a colorless oil. 1H NMR (250 MHz, DMSO-ab) b 8.17 (a, U - 8.0 Hz, 1H), 7.53 (y, y 8.0 Hu, 1H), 6.19 - 6.04 (t, 1H) , 4.27 - 4.06 (t, 2H), 2.23 (d, U - 6.1, 4.4 Hz, 2H), 1.96 - 1.78 (t, 2H), 1.55 (5, 9H). MO-IER t/2 calc. 295, 09753, found 296.0 (M--1) k; Retention time: 6.52 min (Method PX 0).

Step 2: 2-Chloro-6-(3,4-dihydro-2H-pyran-b-yl/pyridine-3-carboxylic acid (c) (c)

In va | ex on 9) | - » 9) -

M SI | M SI

Lithium hydroxide monohydrate (468 mg, 11.153 mmol) was added to a solution of tert-butyl-2-chloro-6-(3,4-dihydro-2H-pyran-b6-yl)pyridine-3-carboxylate (320 mg, 1.0711 mmol) in methanol (5 ml), tetrahydrofuran (20 ml) and water (10 ml). The mixture was stirred at 40 "C for 16 hours and cooled to room temperature. The mixture was acidified with 5 95 HCl and extracted with E(OAc (2 x 20 mL). The combined organic layers were washed with brine and dried over Na 2 O 4 , filtered and evaporated to give /2-Chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carboxylic acid (248 mg, 94 95) as a white solid. 1H NMR (250 MHz, OM5O- ab ) b 8.25 (a, y - 8.0 Hz, 1H), 7.55 (a, y - 8.0 Hz, 1H), 6.13, 9 - 4.2 Hz, 1H), 4.21 - 4.12 (t, 2H), 2.24 (d, U - 6.3, 5.8 Hz, 2H), 1.86 (p, U - 5.9 Hz, 2H). MO-IER n/2 calc. 239.0349, found 240.0 (MA1) k; Retention time: 3.95 min. (Method РХ 0).

Stage C: tert--butyl (45)-4-III-C(6-Ce-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carbonyl|isulfamoyl|-2 -pyridylamino|Ipropyl|-2,2-dimethyl-pyrrolidine-1-carboxylate o o o o

Gi M M r

Same Ton nt | and: | 7 th 7 with (c) o - M M ts -ky

M si t

MN MN

5-X 5-X

DA: Huh

Zo To a solution of 2-chloro-6-(3,4-dihydro-2H-pyran-b-yl/pyridine-3-carboxylic acid (349 mg, 1.456 mmol) in THF (8.0 mL) was added carbonyldiimidazole (252 mg , 1.554 mmol), and the mixture was stirred at room temperature for 20 hours. Then tert-butyl (45)-2,2-dimethyl-4-I3-(b-sulfamoyl-2-pyridyl)amino|propyl|pyrrolidine- 1-carboxylate (400 mg, 0.9696 mmol) followed by the addition of UVA (475 μl, 3.176 mmol), and the resulting mixture was stirred for 3 h at room temperature. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was additionally washed with 10 95 aqueous citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered, evaporated, and then purified by silica gel chromatography using a gradient of 100905 hexanes to 100 95 ethyl acetate. The resulting residue was further purified by preparative reverse-phase HPLC phase (column C 18, 30-99 9o acetonitrile in water with the modifier hydrochloric acid) to obtain tert-butyl (4 C)-4-IZ3-(6-C2e-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carbonyl |Isulfamoyl|-2-pyridylIamino|propyl|-2,2-dimethylpyrrolidine-i-carboxylate (140 mg, 23 95) as a white solid. MO-IER Ip/2 calc. 633.2388, found 634.2 (MA) k; retention time: 2.11 min. (Method of RH B).

Stage 4: 2-chloro-6-(3,4-dihydro-2H-pyran-b-yl)-M-((6-I3-(35)-5,5-dimethylpyrrolidin-3-yl|Ipropylamino|- 2-pyridyl|Isulfonyl|pyridine-3-carboxamide (trifluoroacetate salt) (c) o o (c) o o

M i eh M eh | Uh m? | xx

N N

(c; - M (c) - M

M SI M SI

---

MN MN

LEA at xx

Tert-butyl (45)-4-I3-((6-Ce-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carbonyl|isosulfamoyl|-2-pyridylyamino|Ipropyl |-2,2-dimethylpyrrolidine-i-carboxylate (140 mg, 0.2208 mmol) was dissolved in dichloromethane (610.8 μl) and trifluoroacetic acid (681.1 μl, 8.841 mmol) was added to the mixture and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, 1 ml of toluene was added and removed by rotary evaporation (water bath at 45 "C). 1 ml of toluene was again added and removed on a rotary evaporator (water bath at 45 "C), then dried in vacuum, obtaining 2-chloro-6-(3,4-dihydro-2H-pyran-b-yl)-IM-I((6-I3-((C 3)-5,5-dimethylpyrrolidine-3-yl) propylamino|-2- pyridyl|sulfonyl|pyridine-3-carboxamide (trifluoroacetate salt) (162.3 mg, 100 95) as a white solid. MO-IER Ip/2 calcd 533.18634, found 534.3 ( M--1)x; Retention time: 0.52 min. (Method RH A).

Stage 5: (145)-8-(3,4-dihydro-2H-pyran-b-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3 .1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (Compound 303) o o o o o o o

MU M

5 th o - M - ( - 9 ve es

M si

MN

MN

LEA and

NM

Coo)

To a solution of 2-chloro-6-(3,4-dihydro-2H-pyran-b-yl)-M-((6-(3-(35)-5,5-dimethylpyrrolidin-3-yl|propylamino|- 2-Pyridyl|Isulfonyl|pyridine-3-carboxamide (trifluoroacetate salt) (162.3 mg, 0.2204 mmol) in MMP (8.591 mL) was added potassium carbonate (213.8 mg, 1.547 mmol).The mixture was purged with nitrogen for 5 minutes, then heated to 180 "C and stirred overnight.

It was cooled to room temperature, diluted with EOAc, washed with 1 n. HCl, dried (sodium sulfate), filtered and concentrated to a brown oil, which was filtered and purified by reversed-phase HPLC (C18 column, 1-99 95 acetonitrile in water (5 mM HCl)) to give a white solid (145)-8- (3,4-dihydro-2H-pyran-b-yl)-12,12-dimethyl-2Ab-thia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10)htetracose- 1(22),5,7,9,19(23),20-hexane-2,2,4-trione (3.31 mg, C 90). IN NMR (400 MHz, DMSO-46) b 12.50 (5, 1H), 7.66 (a, 9 - 7.9 Hz, 1H), 7.57 (I, U - 7.9 Hz, 1H), 7.04 (a, 9 - 7.1 Gu , 1H), 6.98 (5, 1H), 6.76 (a, 9 - 8.0 Hz, 1H), 6.70 (a, 9 - 68.5 Hz, 1H), 5.94 (5, 1H), 4.11 (5, 2H), 3.92 (8, U - 11.68 Hu, 1H), 3.11 (5, 1H), 2.93 (8, U -13.1 Hz, 1H), 2.66 (5, 1H), 2.20 (a, 9 - 5.3 Hu, 2H), 2.09 (5, 1H), 1.83 (a, U - 5.9 Hz, ЗН), 1.73 (5, 1Н), 1.61 (5, 1Н), 1.57 (5, ЗН), 1.52 (5, 1Н), 1.49 (5, ЗН), 1.29 (y, У - 12.2 Hz, 1Н), 1.24 (5, 1Н). MO-IER t/2 calc. 497.2097, found 498.1 (Ma-1)xk; retention time: 1.98 min. (Method of RH B).

Example 199: Preparation of 8-I3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-16,16-difluoro-12,12-dimethyl-2A6-thia- 3,9,11,18,23-pentaazatetracyclo|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( enantiomer 1) (compound 305, NCR peak 1) and 8-I3-(2-idispiro(2.0.2.1|)heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-16,16-difluoro- 12,12-dimethyl-2Abthia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane - 2,2,4-trione (enantiomer 2) (compound 304, peak 2 of NKRX) - (c) -- o u o M

Чий и - си b--о зиер2 и хи ов 9) (c) g и Kho Shk s M /"7 (c) (c)

IS

You - and 5ier With What

M - MNVp, ---d-k Ka t m o o

M x ( 7 on

EE

5 January 4 at 5 January 5 to -- - tt E --

Vp, M Ge) MVP.

IS

4 (6) t 5ivrb y 5ier 7 o) ra i t y Ge) ma o E

EE also E MV, (c) E rylo)

Vp, M

MV.

ny zier 8 E zier9 that 5ier 10 VosmM -- E -- it is ----o E (9) o E o E

Vp.M

Vp.M Vp

VosmM VosM hu osi 5ier 11 -- z o E E z | ro J 5ier 12

IS

E M o -- 5 E NM / their nm M- o -

Vp 87

ON X,

GI o s o o o

U on X x / M vm M y M 5 mo. ru with her MN zier 13 | N ia M si y -- - - 5-4 Mo M d- MN

IS

Vos ME

MVos bo

M

ШЕ m7З --- (c) M N y - whether yours sh ЖХ 14 5ier 15 vir 5-0 M s M ikh E d- MN epapioteg 1

IS

Well, because

M gne MN 7 m" S

M. N

. M

MN new,

And her epapioteg 2

Stage 1: 1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one o -o

NM

----I хк (in)

M

SI

(in)

The reaction was carried out in two batches.

Batch 1: A solution of 5,5-dimethylpyrrolidin-2-one (121 g, 1.0693 mol) in DMF (1.8 L) was cooled to 3 °C in an ice-water bath, then 60 95 Man in mineral oil (64.150 g, 1.6039 mol) was added portionwise over approximately thirty minutes. The mixture was stirred in an ice-water bath for an additional thirty minutes, then at room temperature for 1.5 hours. The resulting off-white suspension was again cooled to 3°C in a bath of ice water, then 1-(chloromethyl)-4-methoxybenzene (251.19 g, 1.6039 mol) was added. The ice water bath was removed after the addition and the mixture was stirred overnight.

The reaction mixture was carefully quenched with water (100 mL) and stored in the freezer overnight. The mixture was combined with the second batch of material before processing and cleaning.

Batch 2: a solution of 5,5-dimethylpyrrolidin-2-one (484 g, 4.2772 mol) in DMF (7.2 L) was cooled to 3 "C in a 20 L jacketed reactor, then 60 95 Man in mineral oil (256.61 g, 6.4158 mol) was added in portions over a four-hour period. The resulting mixture was stirred at 3 "C for an additional hour, then at room temperature for two hours.

The resulting suspension was recooled to 3°C, then 1-(chloromethyl)-4-methoxybenzene (1.0048 kg, 6.4158 mol) was added. The cooling system was turned off after the addition was complete, and the resulting suspension was stirred overnight while it was allowed to allowed to warm to room temperature. The reaction mixture was carefully quenched with water (500 mL), combined with the reaction mixture of batch 1 and divided into two equal portions. Each portion was treated as follows: it was diluted with saturated ammonium chloride (10 L), then extracted with ethyl acetate (4 x 2 L). The aqueous phase was discarded, and then the combined organic phases were diluted with hexane (2 L) and extracted with saturated ammonium chloride (2 x 2 L), then with water (2 L). The aqueous phases were discarded, and the organic phase The combined organic phases from both treatments were concentrated in vacuo to give crude 1-((4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one as a brown oil (1.5 kg). One kilogram of crude product was purified by chromatography on silica gel (0-100 95 ethyl acetate:hexane) to obtain pure 1-((4-methoxyphenyl)methyl)|-5,5-dimethylpyrrolidin-2-one (608 g, 58 90) as a yellow oil. MO-IER t/2 calc. 233.1416, found 234.3 (M--1) k; Holding time: 3.97 min. (Method РХ 0).

Stage 2: 3-diethoxyphosphoryl-1-((4-methoxyphenyl)methyl)|-5,5-dimethylpyrrolidin-2-one -o p

T I Y si-v-o i o R. o i U o o-

M /" (c)

Zo A solution of diisopropylamine (529.14 g, 732.88 ml, 5.2292 mol) in tetrahydrofuran (3.5 L) was cooled to -75 "C in a dry ice-acetone bath, then M-butyllithium (2.092 L 2, 5 M, 5.2292 mol) was added in a slow stream. During the addition, the temperature was maintained below -70 "С. The resulting yellow solution was stirred for thirty minutes, then a solution of 1-C4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one (488 g, 2.0917 mol) in tetrahydrofuran (1.5 L) was added slowly and then stirred for another hour. During the addition, the temperature was not allowed to exceed -70 "C. To the reaction mixture, 1-

Chloro(ethoxy)phosphorite|oxyethane (541.38 g, 451.15 mL, 3.1376 mol), taking care to keep the temperature below -70 °C during the addition. The resulting mixture was stirred for sixteen hours, allowing it to thaw to room temperature. The reaction was then quenched with 1 M hydrochloric acid (3 L) and extracted with ethyl acetate (2 x 2.4 L). The aqueous phase was discarded and the combined organic phases were extracted with water (3 x 2.4 L). phases were discarded, and the organic phase was dried over sodium sulfate and purified by chromatography on silica gel (0-100 95 ethyl acetate/hexane), and then concentrated in vacuo to obtain 3-diethoxyphosphoryl-1-((4-methoxyphenyl)methyl |-5.5 -dimethylpyrrolidin-2-one (677 g, 81 95). MO-IER t/2 calcd. 369.1705, found 370.1 (M--1)k; Retention time: 4.2 min. (Method РХ 0 ).

Stage 3: M-(benzotriazol-1-ylmethyl)-M-benzyl-1-phenylmethanamine

Vp.M m Sh // M

M ti - MNVp, -- --- / in x M

M. H

S M on

To a solution of benzotriazol-1-ylmethanol (30 g, 201.14 mmol) in EN (600 mL) was added M-benzyl-1-phenylmethanamine (39.680 g, 38.674 mL, 201.14 mmol) at room temperature. The solution was stirred at room temperature for 1 hour, and then concentrated ip massio.

The residue was washed with diethyl ether (3 x 400 ml) to obtain M-(benzotriazol-1-ylmethyl)-

M-benzyl-1-phenylmethanamine (59.83 g, 91 95) as a white solid. 1H NMR (250 MHz,

SOSIZ) b 7.67 - 7.23 (t, 14Н), 5.47 (5, 2Н), 3.79 (5, AN).

Stage 4: ethyl 3-(dibenzylamino)-2,2-difluoropropanoate

IS

Vp.M -sch TU r

M (c) // o o ' M -- y

And with r"

Vp, M

To a suspension of 2n (17.3 g, 2.4253 mL, 264.57 mmol) in THF (175 mL) was added TM5-CI (28.691 g, 33.4 mL, 264.09 mmol), and then ethyl-2- bromo-2,2-difluoroacetate (11.850 g, 7.5 mL, 58.380 mmol) at room temperature. The solution was stirred for 15 minutes, after which M-(benzotriazol-1-ylmethyl)-M-benzyl-1-phenylmethanamine (17.344 g, 52.812 mmol) in THF (100 mL) was added dropwise to the reaction mixture. The combined solution was stirred for 2 hours, then quenched with sodium bicarbonate (350 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (750 mL) and dried over sodium sulfate before concentration in vacuo. The organic residue was purified by silica gel chromatography, eluting with 0-15 95 diethyl ether in hexane, to give ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (8.98 g, 49 95) as a clear liquid. 1H NMR (500 MHz, OM5O-ab) 6 7.37 - 7.29 (t, 4H), 7.29 - 7.22 (t, 6H), 4.13 (d, y - 7.1 Hz, 2H), 3.61 (5, 4H), 3.15 ( Her, U) - 13.5 Hz, 2H), 1.13 (, U - 7.1 Hz, ZN). MO-

IER t/2 calc. 333.154, found 334.5 (M--1)k; retention time: 3.18 min. (The method of RH R).

Stage 5: 3-(dibenzylamino)-2,2-difluoropropanal 9 E

E ---zh- tour

E (in)

Vp.M

VpoM

To a solution of ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (9.01 g, 27.027 mmol) in anhydrous OSM (125 ml) was added dropwise diisobutylaluminum hydride (37.8 ml of 1 M, 37.800 mmol) at -78 " C. The reaction mixture was stirred for 40 minutes, and then quenched with citric acid (100 ml) at -78 °C. The solution was extracted with diethyl ether (3 x 200 mL), washed with brine (200 mL), and dried over sodium sulfate before concentration in vacuo to give 3-(dibenzylamino)-2,2-difluoropropanal (9.54 g,

From 93 95). MS-IER n/2 calc. 289.1278, found 290.2 (M.-1) housing; retention time: 2.39 min. (The method of RH

R).

Stage 6: 3-3-(dibenzylamino)-2,2-difluoropropylidene-1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one b21

/ oh because

IS

DO I - -

M M

Vp.m E u o Zh

And in Ma o Mp,

OIEA (5.1 g, 6, 8733 mL, 39.461 mmol) and HICI (1.7 g, 40.100 mmol) at 0 °C. The solution was stirred at this temperature for 30 minutes before the addition of 3-(dibenzylamino)-2,2-difluoropropanal (9.544 g, 32.988 mmol) in AFM (50 ml) at 0 "С. The mixture was warmed to room temperature with stirring overnight. The solution was quenched with saturated ammonium chloride solution (150 ml), then extracted with diethyl ether (3 x 200 ml) and washed with brine (300 ml), then dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 0-25% ethyl acetate in hexane, to give 3-(3-(dibenzylamino)-2,2-difluoropropylidene|-1-((4-methoxyphenyl)methyl)|-5.5 -dimethylpyrrolidin-2-one (mixture of E/2-isomers) (8.03 g, 48 95). LIN NMR (250

MHz, SOSIZ) b 7.36 - 7.22 (t, 10H), 7.21 - 7.15 (t, 2H), 6.89 - 6.72 (t, 2H), 6.67 - 5.75 (t, 1H), 4.54 - 4.16 (t, 2H), 3.85 - 3.60 (t, 7H), 3.60 - 3.45 (t, 1H), 3.19 - 2.79 (t, 1H), 2.57 - 2.33 (t, 2H), 1.22 - 0.98 (t, 6H). MO-IER t/2 calc. 504.2588, found 505.2 (M--1); retention time: 3.02 min., 3.51 min. (The method of RH R).

Stage 7. 3-3-(dibenzylamino)-2,2-difluoropropyl|-1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one b u o

And E

M xx 6) Mp, E

E about E

VpoM

To a solution of /3-III-(dibenzylamino)-2,2-difluoropropylidene-1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one (8 g, 15.854 mmol) in ethanol (400 mL) Raney nickel (8 g, 136.30 mmol) was added. The resulting solution was hydrogenated in Wright-Package at 65 lb/sq. inch for 24 hours, then filtered through celite and washed with ethanol to give the crude product. The crude product was purified by flash chromatography (loaded into CH2Cl2) (220 g ZIO2, elution from 0 to 20 95 acetone in hexane) to give 3-IZ3-(dibenzylamino)-2,2-difluoropropyl|-1-(4-methoxyphenyl) methyl|-5,5-dimethylpyrrolidin-2-one (4.97 g, 56 90) as a pale yellow liquid. 1H NMR (250 MHz, SOSIZ) b 7.43 - 7.29 (t, TON), 7.22 (a y - 8.6 Hz, 2H), 6.84 (a, 9 - 68.6 Gu, 2H), 4.38 (5, 2H), 3.81 ( 5, ЗН), 3.78 - 3.50 (t, 6Н), 2.97 - 2.74 (t, ЗН), 2.61 - 2.44 (t, 1Н), 2.21 - 2.01 (t, 1Н), 1.16 (5, ЗН), 0.93 ( 5, ZN). MO-IER tp/2 calc. 506.2745, found 507.2 (MAT) xx; Holding time: 5.75 min. (Method РХ 0).

Stage 8: 3-3-(dibenzylamino)-2,2-difluoropropyl|-5,5-dimethylpyrrolidin-2-one

E And about E

Sodoyuya hody in; MV, (c) (c)

TEA was added to 3-3-(dibenzylamino)-2,2-difluoropropyl|-1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one (4.97 g, 8.9271 mmol) in a vessel (100 ml), then the vessel was closed and heated at 100 "C for 11 days. All solvents were removed under reduced pressure. The residue was dissolved in dichloromethane (300 ml), washed with a saturated aqueous solution of sodium bicarbonate (3 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (loaded into CH 2 CI 2 ) (120 g 5IO 2 , elution from 0 to 4595 ethyl acetate in hexane)) to obtain // 3-IZ-(dibenzylamino )-2,2-difluoropropyl|-5,5-dimethylpyrrolidin-2-one (2.28 g, 66 95) in the form of a pale yellow liquid. MSO-IER tp/2 calcd. 386.217, found 387.3 (M "-1) k; Retention time: 3.29 min. (Method РХ 0).

Step 9: N,M-dibenzyl-3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropan-1-amine

E in lo 60 Nm

NM Men, MVP, (c)

To a stirred solution of 3-(3-(dibenzylamino)-2,2-difluoropropyl|-5,5-dimethylpyrrolidin-2-one (2.23 g, 5.7701 mmol) in anhydrous THF (100 ml) at 0 "С under a nitrogen atmosphere, a solution of VNZ3Me25 (40 mL of 2 M, 80,000 mmol) in THF was slowly added. After the addition was complete, the reaction mixture was heated to 65 °C for 24 hours. The reaction mixture was cooled to 0 °C and slowly quenched with 6 M aqueous NH (50 mL ). Methanol (50 ml) was added and the reaction mixture was heated to 65"C for 1 hour. After cooling to room temperature, the reaction mixture was basified with saturated aqueous Mansoze (300 ml) and the volatiles were removed in vacuo. The product was extracted with ethyl acetate (3 X 150 ml ).The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 1-amine (2.46 g, quant.) as a yellow oil. This product was carried to the next step without further purification. MOS-IER t/: calcd. 372.2377, with found 373.4 (M--1)k; Holding time: 3.87 min. (Method РХ 0).

Stage 10: tert-butyl 4-I(3-(dibenzylamino)-2,2-difluoro-propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate in E in -- --

Nm Mp, Eight MV,

To a stirred solution of M,M-dibenzyl-3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropan-1-amine (2.46 g, 5.9437 mmol) in OSM (80 ml) at Triethylamine (1.0164 g, 1.4 mL, 10.044 mmol) was added at 0 "C, followed by Bos2O (1.96 g, 8.9807 mmol). The reaction mixture was stirred at this temperature for 1 hour. The reaction was quenched with brine ( 100 mL) and then warmed to room temperature The two layers were separated and the aqueous layer was extracted with OCM (2 x 50 mL).

The combined organic layers were dried over anhydrous sodium sulfate and concentrated.

The crude product was purified by chromatography on silica gel using a gradient of 0-15% ethyl acetate in hexane to give tert-butyl-4-3-(dibenzylamino)-2,2-difluoropropyl|-2,2-dimethylpyrrolidine-1-carboxylate (2.79 g, 94 95) in the form of a colorless oil. MSO-IER t/2 calc. 472.2901, found 473.5 (M.-1) k; Holding time: 7.45 minutes. (Method РХ 0).

Stage 11: tert-butyl 4-(3-amino-2,2-difluoro-propyl)-2,2-dimethyl-pyrrolidine-1-carboxylate ve ve

VosM MP, VosM MN,

To a stirred solution /tert-butyl-4-3-(dibenzylamino)-2,2-difluoropropyl|-2,2-dimethylpyrrolidine-1-carboxylate (2.68 g, 5.6706 mmol) in anhydrous methanol (60 ml) palladium on carbon (2.1 g, 10 9o wt., 1.9733 mmol) was added at room temperature under a nitrogen atmosphere, followed by ammonium formate (3.6 g, 57.092 mmol). The reaction mixture was heated to 65" for 6 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite. The filter cake was washed with methanol (2 x 30 mL), and the combined filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography, using a gradient of 0-10 95 methanol in dichloromethane to give tert-butyl-4-(3-amino-2,2-difluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.34 g, 77 95) as of yellow oil. 1N

NMR (250 MHz, SOSIZ) b 3.87 - 3.66 (t, 1H), 3.32 (5, ЗН), 3.13 - 2.86 (t, ЗН), 2.52 - 2.32 (t, 1Н), 2.08 - 1.79 (t, ЗН) , 1.57 - 1.24 (t, 15Н). MO-IER t/2 calc. 292.1962, found 293.5 (Ma) k;

Holding time: 3.55 min. (Method РХ 0).

Step 12: tert-butyl 4-(2,2-difluoro-3-(b-sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate

VosM ro vosm o

E shi a a anna vod

M zo ra

ON h

To a stirred solution of tert-butyl-4-(3-amino-2,2-difluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.24 g, 4.2413 mmol) and 6-fluoropyridine-2-sulfonamide ( 1.12 g, 6.3934 mmol) in anhydrous DMSO (7 mL) at room temperature under a nitrogen atmosphere was added OIEA (1.7020 g, 2.3 mL, 13.169 mmol). The reaction mixture was heated to 120 °C for 30 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and brine (150 mL), and the product was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine. solution (50 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reversed-phase HPLC using a water-acetonitrile gradient method (Magiap C18 column, 50-90 95 acetonitrile, 60 ml/min) to obtain tert-butyl- 4-(2,2-difluoro-3-((b-sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate) (574 mg, 29 95) as a white foam. 1H NMR ( 500 MHz, OM5O-ab) b 7.58 (aa, 9 - 8.4, 7.2 Hz, 1H), 7.37 (I, 9 - 6.4 Gu, 1H), 7.16 (5, 2H), 7.06 - 7.00 (t, 1H), 6.75 (a,

U 8.7 Hu, 1H), 3.96 - 3.81 (t, 2H), 3.64 - 3.51 (t, 1H), 2.83 (d, U - 10.4 Hu, 1H), 2.42 - 2.29 (t, 1H), 2.10 - 1.82 ( t, ЗН), 1.54 - 1.42 (t, 1Н), 1.41 - 1.30 (t, 12Н), 1.23 (5, ЗН). MO-IER t/2 calc. 448.1956, found 449.2 (M.1) k; retention time: 2.38 min. (The method of RH R).

Stage 13: tert-butyl 4-I(3-I((6-(2-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridin- 3-carbonyl|sulfamoyl|-2-pyridylamino|-2,2-difluoro-propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate (9) o te (9) o o

Her o um Myto and E her --yayah M | 2nd - th M M (about what E I In 5 ;

ME

Vos

MVos

2-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (457 mg , 1.270 mmol) and anhydrous THF (8 mL). SOY (355 mg, 2.189 mmol) was added and the mixture was stirred under nitrogen at room temperature for 15 hours. In a separate 20 ml flask, a solution of tert-butyl-4-(2,2-difluoro-3-(b-sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate (570 mg, 1.271 mmol) in anhydrous THF (4 mL) was prepared under nitrogen and then added via syringe to the activated ester solution. OVI (0.78 mL, 5.216 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen for 5 h . The solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (35 mL) and water (35 mL). HCl (1.5 mL 6 M, 9,000 mmol) was slowly added (final pH 5) and the two phases were separated. The aqueous phase extracted EAs (30 ml).

The combined extracts were washed with saline (30 ml) and dried over sodium sulfate.

After evaporation of the solvents, the residue was dissolved in OSM and purified by flash chromatography on silica gel (80 g gold column) using a gradient of ethyl acetate (0 to 100 95 over 30 min) in hexane. The product was eluted with 45-65 95 EOAc. The pure fractions were combined and the solvents were evaporated to obtain tert-butyl-4-I3-(6-C2-chloro-6-(3-(2-dispiro|2.0.2.1|)heptan-7-ylethoxy)pyrazole-1- yl|pyridine-3-carbonyl|sulfamoyl|-2-pyridyl|amino|-2,2-difluoropropyl/|-2,2- dimethylpyrrolidine-1-carboxylate (667 mg, 66 95) in the form of a colorless resin. t/: calculated 789.2887, found 790.54 (M--1)k, retention time: 2.51 min (Method RH B).

Stage 14: 2-chloro-M-I((6-((3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoro-propyl|amino|-2- pyridyl|sulfonyl|-6- (3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt)

POM OM

DOS sat 5-47 My Gay - 5-47 MU si -Ky -- MN sh- MN i E 5 E

E E

MvVos of the 2nd MN

Tert-butyl-4-I(3-I((6-Ce-chloro-6-IZ3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridin- 3-carbonyl|sulfamoyl|-2-pyridylyamino|-2,2-difluoropropyl|-2,2-dimethylpyrrolidine-1-carboxylate (667 mg, 0.8440 mmol), OSM (8 ml) and NSI (1.25 ml 4M in dioxane, 5,000 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexane and the solvents were evaporated. The operation was repeated until a nice white solid was obtained. Drying in vacuo gave 2-chloro-M-I((6-I((3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropyl|amino|-2-pyridyl|sulfonyl/|-6-(3- (2-dispiro|2.0.2.1|heptane-7-

Z oylethoxy)pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) (570 mg, 89 95) as a white solid. MO-IER t/2 calc. 689.23627, found 690.3 (M--1) k; retention time: 1.77 min. (Method of RH B).

Stage 15: 8-I3-(2-I(dispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-16,16-difluoro-12,12-dimethyl-2A6b- thia-3,9,11,18,23-pentaazatetracycloi|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4- trione (enantiomer 1) (Compound 305, NCR peak 1) and 8-I3-(2- ydispiro(2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-16,16-difluoro -12,12-dimethyl-2Ab6-thia-3,9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23), 20-Hexane-2,2,4-trione (enantiomer 2) (Compound 304, peak 2 NCR)

M

Mu 0-y 7 m

M. d M E i M SI - n-N I YA y E - MN epapioteg 1

IS

M gne Ky and sorghum o-Y Ty M m, Zh

IS

E epapioteg2

2-chloro-M-(6-((3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropyl|amino|) was charged into a 100 ml round-bottomed flask equipped with a magnetic stirrer under a nitrogen atmosphere) -2- pyridyl|sulfonyl|-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxamide 5 (dihydrochloride salt) (570 mg, 0, 7469 mmol), anhydrous MMR (24 ml) and K2SOZ (766 mg, 5.542 mmol) (325 mesh). The mixture was intensively stirred in a dry bath at 150 "С under a nitrogen atmosphere for 18 hours. After cooling to room temperature, the mixture was poured into a cooled water (200 mL) and acidified by adding HCl (2 mL, 6 M, 12.00 mmol) (slight foaming).

The resulting solid was filtered on a Buchner funnel and briefly air-dried.

The solid was dissolved in OSM and a small amount of methanol, and the resulting cloudy solution was evaporated. The product was purified by flash chromatography on silica gel (40 g gold column) using a methanol gradient (0 to 55905 in 30 min) in dichloromethane. The product eluted about 195 methanol. Evaporation of solvents followed by rubbing in

OSM/hexanes and solvent evaporation gives racemic 8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-ylI|-16,16-difluoro-12,12-dimethyl -2A6-thia-3,9,11,18,23- pentaazatetracycloly 1 7.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2 ,2,4-trione (404 mg, 83 90) as an off-white solid. MO-IER t/72 calc. 653.2596, found 654.33 (MAT) k; Holding time: 2.34 min. (Method of RH B).

The two enantiomers were separated by chiral NCR using a SpigaIRak A5-3 (250 x 21.2 mm), 5 μM column at 40 "C, mobile phase 24 95 Meon (without modifier), 76 95

CO2, flow: 70 mL/min, concentration: 31 mg/mL in Meon, injection volume: 500 µL, pressure: 156 bar, wavelength: 280 nm. After evaporation of the solvents, each of the enantiomers was purified a second time by flash chromatography on silica gel (24 g column) using a methanol gradient (from 0 to 5 95 in 30 min) in dichloromethane. After evaporation of the solvents, the compounds were triturated in PCM/hexane. Evaporation of the solvents gives two enantiomers as white solids.

Compound 305, peak 1 of NKRKH. ee" 98 Fr. 8-I3-(2-dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|I-16,16-difluoro-12,12-dimethyl-2A6-thia-3,9 ,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

Zo (enantiomer 1) (174 mg, 70 90). 1H NMR (500 MHz, OM5O-ab6) b 12.54 (5, 1H), 8.22 (a, y - 2.8 Hz, 1H), 7.87 (a, 9U - 8.2 Hz, 1), 7.71 (1, 9 - 7.9 Gu , 1H), 7.52 (a, U - 10.2 Hz, 1Hn), 7.22 (a,9 - 7.2 Hu, 1H), 6.96 (a, U - 68.3 Hz, 2H), 6.10 (a, 9 - 2.7 Hu 1H), 4.48 (i, 9 - 37.1, 12.7 Hz, 1H), 4.22 (I, 9 - 6.68

Gu, 2H), 3.30 (rgoai 5, 1H), 3.12 (I, U - 8.6 Hz, 1H), 2.77 (I, U - 10.6 Hz, 1H), 2.39 (Bug 5, 1H), 2.27 - 2.03 (t . (5, ZN), 1.48 (I, U - 6.6 Hz, 1H), 0.90 - 0.75 (t, 4H), 0.69 - 0.60 (t, 2H), 0.55 - 0.39 (t, 2H). MO-IER t/2 calc. 653.2596, found 654.33 (MAT) k; retention time: 2.34 min. (The method of RH

IN).

Compound 304, peak 2 of NKRKH. ee" 98 Fo. 8-I3-(2-Idispiro (2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|I-16,16-difluoro-12,12-dimethyl-2A6-thia-3 ,9,11,18,23- pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione ( enantiomer 2) (178 mg, 71 90). 1H NMR (500 MHz, OM5O-ab6) b 12.53 (5, 1H), 8.22 (a, y - 2.8 Hz, 1H), 7.87 (a, 9U -8.2 Hz, 1), 7.71 (1, 9 - 7.9 Gu , 1H), 7.52 (y, U - 10.1 Hu, 1H), 7.21 (a, 9 - 7.2 Hz, 1H), 6.96 (a, U - 68.3 Hz, 2H), 6.10 (a, 9 - 2.7 Hu, 1H ), 4.48 (a, 7 - 37.3, 12.4 Hz, 1H), 4.22 (1.9 6.7

Gu, 2H), 3.30 (rgoai 5, 1H), 3.12 (I, U - 8.6 Hz, 1H), 2.77 (I, U - 10.6 Hz, 1H), 2.39 (Bg 5, 1H), 2.26 -

2.05 (t, 2H), 1.93 (da, U - 12.0, 5.2 Hz, 1H), 1.82 (d, U - 6.6 Hz, 2H), 1.72 (I, U - 12.4 Gu, 1H), 1.64 (5, ZN ), 1.54 (5, ZN), 1.48 (I, U - 6.6 Hz, 1H), 0.90 - 0.77 (t, 4H), 0.72 - 0.60 (t, 2H), 0.56 - 0.45 (t, 2H). MO-IER t/2 calc. 653.2596, found 654.33 (M'-1)k; retention time: 2.34 min. (The method of RH

IN).

Example 200: Preparation of 8-I3-(2-I(idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-yl|-16-fluoro-12,12-dimethyl-2A6-thia- ( enantiomer 1) (compound 309, NCR peak 1), 8-I3-(2-idispiro|2.0.2.1|)heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-16-fluoro-12, 12-dimethyl-2Abthia-3,9,11,18,23- pentaazatetracyclo!i17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane- 2,2,4-trione (enantiomer 2) (compound 308, NCR peak 2), 8-I3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-16 -fluoro-12,12-dimethyl-2Abthia-3,9,11,18,23- pentaazatetracyclo!y17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23) ,20-hexane-2,2,4-trione (enantiomer 3) (compound 307, peak 3 NCR) and 8-I3-(2-ydispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazole- 1-yl1-16-fluoro-12,12-dimethyl-2Abthia-3,9,11,18,23-pentaazatetracycloyl17.3.1.111,14.05,10|hetracose-1(22),5,7,9 ,19(23),20-hexane-2,2,4-trione (enantiomer 4) (Compound 306, NCR peak 4) / -oo o / shi zier 1 , M vier2 ni zier Z Vosu

M -80-- -- ;- ---ейюх г (е) о хх х хх

MN Vosm

Eight o-y--o 5ier 4 E zier 5 eighth zier 6 - oo - p in

Ve | nm

Vg E and j o-v-MNn,

HER

(9)

It is 3 Ω

M

SS that - mouth"

M ME si Ge) is MN vir 7 m | r n Ii r 5ier 8 o-4fyi dom M si 06020027 o E ze In

IS

Vos ME

MVos dere pe de pt r o CHI, CHO, (M van den - M si - -- Shchi g g sl Y M -- sa Y M 4 -

Stage 1: 3-allyl-1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one

CI

She - Vg gives M i ; " (c) (c)

XX

A solution of diisopropylamine (4.3372 g, 6.0 mL, 42.862 mmol) in tetrahydrofuran (100 mL) was cooled to -78 °C and M-butyllithium (17.1 mL, 2.5 M, 42.862 mmol) was added dropwise.

The solution was stirred for thirty minutes, then a solution of /-1-((4-methoxyphenyl)methyl)|-5,5-dimethylpyrrolidin-2-one (10 g, 42.862 mmol) in THF (10 mL) was added dropwise, and then stir for an hour. 3-bromoprop-1-ene (5.1853 g, 3.71 mL, 42.862 mmol) was added dropwise to the reaction mixture, stirred for one hour at -78 °C, and then allowed to warm to 0 °C for 30 minutes. The reaction was then quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over sodium sulfate and purified by chromatography on silica gel (0-20 95 ethyl acetate/hexane) to give 33-allyl-1-((4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one ( 8.75 g, 71 90). MO-IER t/72 calcd. 273.1729, found 274.0 (M--1) g; retention time: 2.97 min. (Method RH R).

Stage 2: 3-allyl-5,5-dimethyl-pyrrolidin-2-one / (c)

M --3 (c) (c) d i:

3-allyl-1-(4-methoxyphenyl)methyl|-5,5-dimethylpyrrolidin-2-one (7.75 g, 28.350 mmol) was dissolved in acetonitrile (140 mL) and water (16 mL), then in ceric acid . Ammonium nitrate (64.559 g, 113.40 mmol) was added portionwise at room temperature, and the reaction mixture was stirred for 3 hours. Then it was quenched with saline solution (300 ml) and extracted

EtOAc (C x 150 ml). The organic fractions were combined, dried over sodium sulfate and evaporated, the residue was purified by chromatography on silica gel using 0-100 90 hexanes-ethyl acetate to obtain 3-allyl-5,5-dimethylpyrrolidin-2-one (3.77 g, 76 95 ). MO-IER t/2 calc. 153.1154, found 154.2 (M.-1) k; retention time: 1.61 min. (The method of RH R).

Stage 3: tert-butyl 4-allyl-2,2-dimethyl-pyrrolidine-1-carboxylate

Lo -- VosmM i sh kh i ra

A solution of 3-allyl-5,5-dimethylpyrrolidin-2-one (3.77 g, 24.605 mmol) in THF (25 mL) under reflux. The mixture was heated at reflux for 3 hours, cooled to 0 °C, and then water (2.8 mL) was added very slowly, followed by sodium hydroxide (2.8 mL) and water (8.4 mL). The mixtures were allowed to warm to room temperature and added

Bos20O (6.4440 g, 6.7832 mL, 29.526 mmol) The mixture was stirred for 16 hours, filtered, and the precipitate on the filter was triturated with THF. The organic fractions were combined and evaporated, the residue was purified by chromatography on silica gel using 0-5 95 ethyl acetate in hexane to give tert-butyl-4-allyl-2,2-dimethylpyrrolidine-1-carboxylate (5.06 g, 77 95 ). IN NMR (250

MHz, Spiogoitogit-a) 6 5.93 - 5.58 (t, 1H), 5.15 - 4.89 (t, 2H), 3.82 - 3.48 (t, 1H), 2.90 (d, U -10.9

Gu, 1), 2.32 - 1.97 (t, ZN), 1.94 - 1.75 (t, 1H), 1.50 - 1.25 (t, 16H). MO-IER t/2 calc. 239.1885, found 240.3 (MAT) k; Holding time: 3.53 min. (The method of RH R).

Stage 4: tert-butyl 4-(3-bromo-2-fluoro-propyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

VosmM pi Te

IS

Hg

Kh

A solution of tert-butyl-4-allyl-2,2-dimethyl-pyrrolidine-1-carboxylate (500 mg, 1.8801 mmol) and triethylamine trihydrofluoride (710 mg, 1.6296 mmol) in OCM (10 mL) was cooled to 0 "C and MV5 (500 mg, 2.8092 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was quenched with saturated sodium bicarbonate (50 mL), the aqueous phase was separated and extracted with OSM (100 mL). Organic fractions combined, dried over sodium sulfate and evaporated. dimethylpyrrolidine-1-carboxylate (420 mg, 65 95 ) in the form of a colorless oil. 1H

NMR (250 MHz, SOSIZ) b 4.87 - 4.42 (t, 1H), 3.86 - 3.54 (t, 1H), 3.55 - 3.22 (t, 2H), 3.07 - 2.75 (t, 1H), 2.56 - 2.18 (t, 1H), 2.12 - 1.71 (t, ZN), 1.71 - 1.57 (t, 1H), 1.51 - 1.38 (t, 12H), 1.35 - 1.24 (t, ZN). MO-IER t/2 calc. 337.1053, found 338.5 (M--1)-4; retention time: 3.59 min. (The method of RH R).

Stage 5: tert-butyl 4-(3-amino-2-fluoro-propyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

VosM Vosm 204 Z

Vg Mn,

To a solution of tert-butyl-4-(3-bromo-2-fluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (2.26 g, 6.5477 mmol) in DMF (28 mL) was added Mam with (0, 6 g, 9.1832 mmol), and the mixture was stirred at 45 oC for 18 hours. The mixture was diluted with water (150 mL), then with saturated sodium bicarbonate (150 mL), and the mixture was extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with saline (300 ml), dried over sodium sulfate, filtered and concentrated with

With obtaining the intermediate azide in the form of a brown oil. To a solution of this intermediate azide oil in ethyl acetate (30 mL) was added platinum oxide monohydrate (0.5 g, 2.018 mmol). The mixture was hydrogenated on a Parr shaker at 40 psi. inch for 1 hour. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to obtain tert-butyl-4-(33-amino-2-fluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.59 g, 87 95) as a dark oil. MO-IER t/2 calc. 274.2057, found 275.6 (M'-1)k; Holding time: 3.51 min. (Method РХ 0).

Stage 6: tert-butyl 4-(2-fluoro-3-(b-sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate y" o-55-50

VosM And I

M E - - - ь--- VosM r Mn, y Н M s

E 4 Mn, and To

To a mixture of tert-butyl-4-(3-amino-2-fluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.59 g, 5.6791 mmol) and 6-fluoropyridine-2-sulfonamide (1.3 g, 7.0103 mmol) in DMSO (10 mL) was added

OIEA (2.2260 g, C ml, 17.223 mmol). The mixture was stirred at 110 "C for 16 hours. The mixture was cooled to room temperature and the mixture was treated with water/brine (100/100 mL) and ethyl acetate (150 mL). The organic layer was dried over sodium sulfate, filtered through a pad of celite, and concentrated. The residue (2.1 g, combined with 0.56 g of the product from the previous reaction) was dissolved in DMSO (10 ml) and applied to a column for preparative HPLC (Magiap C18 10 μm 5 x 30 cm; flow rate: 60 ml/min .; mobile phase A: water; mobile phase B: acetonitrile; method: 40-90 95 V for 45 min.) Pure fractions were combined and concentrated to remove acetonitrile.

The obtained aqueous phase was extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with brine (200 ml), dried over sodium sulfate and concentrated to obtain tert-butyl-4-(2-fluoro-3-((b-sulfamoyl-2-pyridyl)amino|propyl|-2,2- dimethylpyrrolidine-1-carboxylate (1.5 g, 58 95) as a white solid. 1H NMR (250 MHz, OM5O-a4a6) b 7.56 (9 - 7.8 Hz, 1H), 7.27 (1.9 - 5.8 Hz, 1H), 7.12 (5, 2H), 7.00 (a, 9. - 7.1 Hz, 1H), 6.71 (a, U - 8.4 Gu, 1H), 4.95 - 4.46 (t, 1H), 3.77 - 3.40 (t, ЗН), 2.95 - 2.73 (t, 1Н), 2.40 - 2.15 (t, 1Н), 2.02 - 1.85 (t, 1Н), 1.83 - 1.57 (t, ЗН), 1.54 - 1.29 (t, 12Н), 1.25 ( 5, ZN). MO-IER t/2 calculated 430.205, found 431.5 (M--1) k, retention time: 2.35 min. (Method RH K).

Stage 7: tert-butyl 4-I3-C(6-Ce-chloro-6-I3-(2-dispiro(2.0.2.1|)heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carbonyl| sulfamoyl|-2-pyridyl|amino|-2-fluoro-propyl|-2,2-dimethyl-pyrrolidine-1-carboxylate p o s o o o

M

5-47 Language E Y -090-05- uk M cho i 4 - ko i. 5 axis M

MVos

2-Chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|Ipyridine-3-carboxylic acid (573 mg , 1.593 mmol) and anhydrous THF (10 mL). SOY (315 mg, 1.943 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours. Another 150 mg of CO1 was added and the mixture was stirred at room temperature for 15 hours until complete conversion. In a separate flask with a volume of 20 ml, a solution of tert-butyl-4-(2-fluoro-3-((b-sulfamoyl-2-pyridyl)amino|propyl|-2,2-dimethylpyrrolidine-1-carboxylate) (693 mg, 1.610 mmol) in anhydrous THF (5 mL) was prepared under a nitrogen atmosphere and then added by syringe to the activated ester solution.YUVY (0.96 mL, 6.419

2 mmol) was added via syringe and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (40 mL) and water (40 mL). NCI (1.8 ml of 6 M, 10.80 mmol) was slowly added (final pH - 5) and the two phases were separated. The aqueous phase was extracted with EOAc (30 mL).

The combined organic extracts were washed with saline (30 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue (1.34 g) was dissolved in OSM and purified by flash chromatography on silica gel (80 g gold column) using a gradient of ethyl acetate (0 to 10095 in 30 min) in hexane. The product is eluted with 45-6595 EOAbs. The pure fractions were combined and the solvents were evaporated to obtain tert-butyl-4-(3-((6-Ce-chloro-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazole-1 -yl|Ipyridine-3-carbonyl|sulfamoyl|-2-pyridylyamino|- 2-fluoropropyl|-2,2-dimethylpyrrolidine-1-carboxylate (804 mg, 6595) as a white foamy solid. . 771.2981, 772.39 (M of 1) were found; Retention time: 2 diastereomers are visible, 1:11, Vi- 2.51 and KG - 2.52 min (RC Method B). The product was used in the next stage without additional cleaning.

Stage 8: 2-chloro-M-(6-((3-(5,5-dimethylpyrrolidin-3-yl)-2-fluoro-propyl|amino|-2- pyridyl|sulfonyl|-6-(3-( 2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt)

(0) oo

M and OM to oo and shsh- MN and o vn

E 5 E

MVos zno MN

Tert-butyl-4-(3-(6-Ce-chloro-6-I3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3) was loaded into a 100 ml flask -carbonyl|sulfamoyl|-2-pyridyl|amino|-2-fluoropropyl/|-2,2- dimethylpyrrolidine-1-carboxylate (782 mg, 1.013 mmol), OSM (9 ml) and NSI (1.5 ml in 4M dioxane, 6.000 mmol). The reaction was stirred at room temperature for about 5 h. Volatiles were removed by evaporation under vacuum. The residue was triturated with Kk dichloromethane/hexane and the solvents were evaporated. The operation was repeated until a beautiful white solid was obtained. Drying in vacuo gave 2-chloro- M-I((6-I((3-(5,5-dimethylpyrrolidin-3-yl)-2-fluoropropyl|amino|-2-pyridyl|sulfonyl/|-6-(3-(2-dispiro|2.0 .2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridine-3-carboxamide (dihydrochloride salt) (731 mg, 97 95) as a white solid.

The product was used in the next stage without additional purification. MO-IER t/2 calc. 671.24567, found 672.44 (M--1); retention time: 1.75 min. (Method of RH B).

Stage 9: 8-I3-(2-isdispiro|2.0.2.1|)heptan-7-yluethoxy)-1H-pyrazol-1-yl|-16-fluoro-12,12-dimethyl-2Ab-thia-3, 9,11,18,23-pentaazatetracyclo!|17.3.1.111,14.05,10|hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 1) (Compound 309, NCR peak 1), 8-I3-(2-Idispiro|2.0.2.1|heptan-7-yl)ethoxy)-1H-pyrazol-1-yl|-16-fluoro-12,12- dimethyl-2A6-thia-3,9,11,18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (Compound 308, NCR peak 2) . 18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 3) (Compound 307, peak C of NCR) and 8-13-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-16-fluoro-12,12-dimethyl-2Ab6-thia-3,9,11, 18,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 4) (Compound 306, NCR peak 4) named after Ya

M Y / moty m y 7 momme me z I Y chn t epapioteg 1 epapioteg 2 5 Y Y Shk epapioteg Z epapioteg 4

2-chloro-M-((6-((3-(5,5-dimethylpyrrolidin-3-yl)-2-fluoropropyl|amino|-) was charged in a 100 ml round-bottomed flask equipped with a magnetic stirrer under a nitrogen atmosphere) 2- pyridyl|sulfonyl|-6-(3-(2-dispiro|2.0.2.1|heptan-7-ylethoxy)pyrazol-1-yl|pyridin-3-carboxamide (dihydrochloride salt) (723 mg, 0.9703 mmol ), anhydrous MMR (30 ml) and K2SOZ (996 mg, 7.207

Zo mmol) (325 mesh). The mixture was intensively stirred in a dry bath at 150 "C in a nitrogen atmosphere for 18 hours. After cooling to room temperature, the mixture was poured into chilled water (300 ml) and acidified by adding HCl (2.5 ml, 6 M, 15.00 mmol) (light foaming).

The resulting solid was filtered on a Buchner funnel and briefly air-dried.

The solid was dissolved in OSM and a small amount of methanol, and the resulting cloudy solution was dried over sodium sulfate. After concentration (910 mg crude solid), the solution was purified by flash chromatography on silica gel (80 g gold column) using a gradient of methanol (0 to 5 95 over 30 minutes) in dichloromethane. The product eluted about 2-3 95 methanol. Evaporation of solvents followed by grinding in

OSM/hexanes and evaporation of solvents gives 8-I3-(2-Idispiro|2.0.2.1|heptan-7-yluethoxy)-1 H-

pyrazol-1-yl|-16-fluoro-12,12-dimethyl-2A6-thia-3,9,11,18,23-pentaazatetracycloyl 1 7.3.1.111,14,05,10)tetracose-1(22 ),5,7,9,19(23)20-hexaene-2,2,4-trione (467 mg, 76 95) (a mixture of 4 isomers) as an off-white solid. 1H NMR (500 MHz, OM5O-ab) earth mega! diastereomer5 oBzegmei b 12.57 apa 12.50 (yugo 5, ioia! 1H), 8.25 - 8.19 (t, 1H), 7.83 (a, 9 - 8.2 Hz, 1H), 7.65 (d, U - 8.0 Gu, 1H), 7.37 - 7.11 (t, 2H), 6.98 - 6.74 (t, 2H), 6.10 (ad, 9 - 4.6, 2.1 Hz, 1H), 4.87 (a, U - 43.7 Hu, 1H), 4.32 - 4.04 (t, ЗН) , 3.29 - 2.97 (t, 2H), 2.92 - 2.60 (t, 1H), 2.47 - 2.23 (t, 1H), 2.18 - 1.76 (t, 5H), 1.75 - 1.44 (t, 8H), 0.87 - 0.77 ( t, 4H), 0.70 - 0.56 (t, 2H), 0.56 - 0.43 (t, 2H). MO-IER t/2 calc. 635.269, revealed 636.37 (M «t 1) ; Retention time: two peaks are visible, CI - 2.32 and CI - 2.34 min (Method RH B).

The four stereoisomers were separated using chiral NCR in two stages. The sample was first purified using a normal-phase NLC-MS method using a column

GOH-4 (250 x 21.2 mm, particle size 5 μm), sold by Rpepotepeh (product code: 000-4491-РО-АЧ).

Mobile phase: 41 95 MeonN (without modifier), 59 95 CO 2, 70 ml/min, 31 mg/ml in Meon, injection volume - 500 μl, column temperature - 40 "С, pressure 178 bar, wavelength 280 nM. This separated peak 1 and peak 2 from peaks C and 4, which eluted together. After evaporation of the solvents, peaks C and 4 (216 mg solid) were separated using a spigaIRak A5

Z (250 x 21.2 mm), 5 µM, mobile phase 28 95 MeOnH (no modifier), 72 95 CO2, 70 mL/min, 31 mg/mL in MeOOnH, injection volume 500 µL, pressure 156 bar, wavelength 280 mm. After evaporation of the solvent, each compound was purified by flash chromatography on silica gel (12 g column) using a gradient of methanol (0 to 595 in 15 minutes) in dichloromethane. For each separated isomer, the solvents were evaporated and the residue was triturated in OSM/hexane.

Evaporation of solvents gives products in the form of off-white solids. Based on the retention time of IC, peak 1/2 and peak 3/4 form enantiomeric pairs. This was confirmed by mixing the QC solution from peak 2 with peak 3, which gave two separate peaks. Superposition of 1H NMR of 4 isomers confirms the observation: peak 1 and 2 have the same 1H NMR spectrum, while peak C of the IN NMR spectrum is identical to peak 4.

Compound 309, peak 1 of NKRKH. ee" 98 Fr. 8-I3-(2-dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-16-fluoro-12,12-dimethyl-2A6-thia-3,9,11,18 ,23- pentaazatetracyclo!|17.3.1.111,14.05,10)hetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione

Zo (enantiomer 1) (98 mg, 61 95). IN NMR (500 MHz, OM5O-a6) 5 12.50 (Bgoaa 5, 1H), 8.22 (5, 1H), 7.82 (Bg 5, 1H), 7.66 (I, U - 7.9 Hz, 1H), 7.24 (Brg 5 . , 1H), 4.22 (rg 5, 2H), 4.12 (Bg 5, 1H), 3.26 - 3.02 (horn t, 2H), 2.82 (ri 5, 1H), 2.44 (ri 5, 1H), 2.08 (horn , 1H), 1.98 - 1.44 (t, 12H), 0.89 - 0.75 (t, 4H), 0.72 - 0.60 (t, 2H), 0.55 - 0.43 (t, 2H). MO-IER t/2 calc. 635.269, found 636.37 (Ma-1); Holding time: 2.33 min. (Method of RH B).

Compound 308, peak 2 of NKRKH. ee" 98 Fr. 8-I3-(2-dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-16-fluoro-12,12-dimethyl-2A6-thia-3,9,11,18 ,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 2) (98 mg, 61 95). IN NMR (500 MHz, OM5O-46) b 12.50 (5, 1H), 8.23 (a, U - 2.68 Hz, 1H), 7.84 (a, 9 - 7.4 Hu, 1H), 7.66 (I, U - 7.9 Hu . 2.7 Hz, 1H), 4.83 (rg a, U - 44.5 Hz, 1H), 4.23 (9 - 6.8, 2.1 Hz, 2H), 4.13 (rg 5, 1H), 3.15 (Brg 5, 2H), 2.82 (Bri 5, 1H), 2.44 (Big 5, 1H), 2.08 (Bg 5, 1H), 1.97 - 1.42 (t, 12H), 0.90 - 0.76 (t, 4H), 0.73 - 0.57 (t, 2H), 0.56 - 0.41 (t, 2H). MO-IER t/: calc. 635.269, found 636.33 (M'-1) k; retention time: 2.33 min. (Method of RH B).

Compound 307, peak Z NKRKH. ee" 98 Fr. 8-I3-(2-dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-16-fluoro-12,12-dimethyl-2A6-thia-3,9,11,18 ,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 3) (90 mg, 56 95). IN NMR (500 MHz, OM5O-46) b 12.57 (5, 1H), 8.21 (a, U - 2.68 Hz, 1H), 7.83 (a, 9U - 68.2 Hz, 1), 7.64 (I, U - 7.9 Hz . 1H), 4.88 (a, 9 - 42.8 Hz, 1H), 4.30 - 4.09 (t, ЗН), 3.36 (t, 1H omeparreid uliy uaieg), 3.01 (I, U - 8.9 Gu, 1H), 2.64 (I, U - 10.7 Hz, 1H), 2.31 (Bgoaay 5, 1H), 1.94 - 1.75 (t, 5H), 1.69 - 1.57 (t, 4H), 1.52 (5, ЗН), 1.48 (I, U - 6.5 Gu, 1H), 0.90 - 0.78 (t, 4H), 0.68 - 0.59 (t, 2H), 0.55 - 0.41 (t, 2H). MO-IER t/: calc. 635.269, found 636.37 (M'-1)k; retention time: 2.3 min. (Method of RH B).

Compound 306, peak 4 of NKRKH. ee" 98 Fr. 8-I3-(2-dispiro|2.0.2.1|heptan-7-yluethoxy)-1H-pyrazol-1-ylI-16-fluoro-12,12-dimethyl-2A6-thia-3,9,11,18 ,23- pentaazatetracyclo!| 1 7.3.1.111,14.05,10)htetracose-1(22),5,7,9,19(23),20-hexane-2,2,4-trione (enantiomer 4) (74 mg, 46 95). IN NMR (500 MHz, OM5O-46) b 12.57 (5, 1H), 8.21 (a, U - 2.68 Hz, 1H), 7.83 (a, 9. - 8.2 Hz, 1), 7.64 (I, U - 7.9 Hz, 1H), 7.33 (rgoai a, U - 9.7 Hz, 1H), 7.13 (a, U - 7.2 Gu, 60 1H), 6.94 (aa, 9 - 10.6, 8.4 Hz, 2H), 6.10 (y, U - 2.7 Hz, 1H), 4.68 (y, U - 43.5 Gu, 1H), 4.28 - 4.08 (t,

ZN), 3.35 - 3.24 (t, 1H omeparrei m magieg), 3.04 - 2.92 (t, 1H), 2.63 (I, U - 10.9 Gu, 1H), 2.31 (Bg 5, 1H), 1.97 - 1.75 (t, 5H), 1.67 - 1.59 (t, 4H), 1.52 (5, ЗН), 1.48 (1.9 - 6.6 Hz, 1H), 0.91 - 0.76 (t,

AN), 0.67 - 0.60 (t, 2H), 0.54 - 0.41 (t, 2H). MO-IER t/: calc. 635.269, found 636.33 (MAT) k; retention time: 2.3 min. (Method of RH B).

Bioactivity assays

Solutions

The basic medium (AOE zh--zh) consisted of Admapsea OMEM/Na!t"5 E12, 2 mM glutamax, mM NEREZ, 1 µg/ml penicillin/streptomycin.

The maintenance medium for intestinal enteroid (CHEMM) consisted of AB, 1 10 supplement B27, 1 supplement M2, 1.25 mM M-acetylcysteine, 10 mM nicotinamide, 50 ng/ml PESBE, 10 nM gastrin, 1 μg/ml pE- spondin-1, 100 ng/ml pModdip, TOB-Br type 1 receptor inhibitor A-83-01, 100 μg/ml primocin, 10 μM RZV inhibitor MARK 58202190.

The buffer for bath 1 consisted of 1 mm MgsI2, 160 mm Masi, 4.5 mm KSI, 10 mm NEREZ5, 10 mm glucose, 2 mm Sasig.

Chloride-free buffer consisted of 1 mM magnesium gluconate, 2 mM calcium gluconate, 4.5 mM potassium gluconate, 160 mM sodium gluconate, 10 mM NEREZ, 10 mM glucose.

Dye solution Wow! consisted of buffer Ba 1, 0.04 95 Riigopis E127, 20 µM methyloxonol, 30 µM CaSsspp-AO1, 30 µM Spisado 5Ku Vispeye.

Chloride-free dye solution consisted of chloride-free buffer, 0.04 95 RiIshgopis E127, 20 µM methyl oxonol, 30 µM SasSypp-AO1, 30 µM Spisado 5Ku Vince.

The chloride-free dye stimulation solution consisted of a chloride-free dye solution, 10 μM forskolin, 100 μM IVMH, and 300 nM of the PP compound.

Cell culture

Epithelial enteroid cells of the human intestine were obtained from the Institute of Developmental Biology and Stem Cell Research named after Hubrecht, Utrecht, the Netherlands, and propagated in T-flasks as previously described (OekKeg5 UR, UMiedegipsk SI, ae dopde NE, Vgopzhmeii I, dapozep5 NM, de M/ipieg-de Stooi KM, Vgapazta AM, de dopud MUUM, Viimeid5 MS, 5spote VU, Miviumepniiv EE5, map dep Viipk 5, Siemeg5 H, map deg Epi SK, Middepdogr 5 apa M VeeeKtap M. Functional analysis of CETC using intestinal organoids of primary cystic fibrosis. May May. 2013

Zo Uy; 19(7):939-45.).

Collection and seeding of enteroid cells

Cells were recovered in cell recovery solution, collected by centrifugation at 650 rpm for 5 minutes at 4 °C, resuspended in TgURI E and incubated for 5 minutes at 37 °C. Then the cells were collected by centrifugation at 650 rpm for 5 minutes at 4 °C and resuspended in IEMM containing 10 μM of the COSC inhibitor (KI) (trans-4-(1A8)-1-aminoethyl|-M-4-pyridinylcyclohexanecarboxamide ).The cell suspension was passed through a 40 μm cell strainer and resuspended at a concentration of 1 x 10 6 cells/ml in IEMM containing 10 μm

CI. Cells were seeded 5,000 cells per well into multiwell plates and incubated overnight at 37 "C, humidity 95 95 and 5 96 CO02 until analysis.

Analysis of membrane potential dye

Enteroid cells were incubated with the test compound in U(EMM) for 18-24 hours at 37" C, humidity 9595 and 595 002. After incubation of the compounds, a transmembrane potential assay with a dye using BHIRE Teia was used to directly measure the activity and efficiency of the test compound against CETK- mediated chloride transport after the rapid addition of 10 μM forskolin and 300 nM compound PI. Briefly, cells were washed 5 times in buffer Ba 1. A solution of dye Ba 1 was added and cells were incubated for 25 min at room temperature. After incubation with the dye, cells were washed 3 times chloride-free dye solution. Chloride transport was initiated by adding chloride-free dye stimulation solution and the fluorescence signal was read for 15 min. CETK-mediated chloride transport for each condition was determined by

AU of the fluorescence response to acute stimulation with forskolin and 300 nM compound I. Chloride transfer was then expressed as a percentage of chloride transfer after treatment with 3 μM

Compounds A, C µM of Compound II and 300 nM of the control triple combination Compound II of acute action ( o

Mn,

Y (Z (c)

M

From X / y m" M

NOT about

E in zd

SHIE activities). Compound a: .

Table 5 shows the results of analyzes of the biological activity of typical compounds according to the invention (maximum activity: ияж-- means" 60 90; и- means 30-60 90; и- means "30 Ob.

ES5BO: with---- "1 MKM; w- means 1-3 µM; zhk» With μM; and HB -- "undefined".)

Table 5

ESCB

Oh oh

X// and m | and

N

1 n.s. M. schu Mykh ni ni

Z o- M M no A MN no 8 no ns (c) o

CT and m | and:

N

2 n.s M. HU M in I with o- M M not in MN no 8 no no

Oh oh

X// and 7 | and:

N

Z Ne M xx M ni nya z o-. / M M M not in MN no -8- no no

Table 5 (continued)

ESBO o o.o

M y M xx shhU | and Y 4 5-47 M M 2-4 ny ny

Е -3О- not МН not

Ee o o o

M y M xx shhhh | and Y 5-47 M M - niya ni

E - no MN no

Eh oh oh

AND

8 and M xx that | y Y 5-47) М M y niks niyinny

E -t6- not MN not

Ee o o o

M and M

N

7 5-47) ve M nn ny

There are so and not so

And sleep, oh oh

M y y

N shkh

E and dO not o is a dream,

Table 5 (continued)

ESBO o o.o

І и M Эх х и І 5-47 M г ж ж

E d - M

And sleep

Oo oo

AND

7th M. E. H. and I

E - M

E sn, (c)

M y M y hu y Y 11 o u M tav - the same; and Y

E ne en, e sn, o oo

M and M x

ХУ и Й 12 o u MM M - v nya y y - not MN

And sleep, oh oh

M y M x xx A Y 13 5-47 M M what 4 we are

E i - ns sn is sn, o

M and g 5

I | - Y 14 5-47 M M 4 niya ny

IY sh- and not MN in a dream,

Table 5 (continued)

ESBO o oo hu y M Uh sce - I 15 5-47 М M - nia ny y -Ons MN sn,

RE in o o

Ha MU ten

M Kho 16 E and She N in same -

Well, we M M - not sleep,

We are 7

SWING

GG

17 MN nok nok im MU M 0th ; And there is no dream,

E o sn o and Z eh sha; nN

IS

18 sleep | ru - z nia

E M

Mk M --a -IKh ne sn, o sn (in; oh z

M topics -x! TO, 19 | ro Mnki z

E M

M M

E 5-4 are happy - not sleep,

Table 5 (continued)

ESCB

9 o//

I re U ; mo 20 U | ro M same c

E M M M

-M and 5-4. glad - not sleep, in! o, /Р и M -х ху А Й 21 5-47 М M 4 ж - и -О- ne МН сн,

Hey in! m and M xx

I A y 22 5-47 М M - ny ny y -- not MN sn,

Ee o o o

M m y y xx

A, 23 o'clock - M M I I and dsch- ne MN and sn,

M us

SWING

2 24 M. - MN nya nya

Kk me there is no

Uk sn,

Table 5 (continued)

ESBO about about

And we are 7

MAH and (in the city of | ru MN nok nia

IS

-- not a dream,

E o c) o scha y:

E and 26 | ru M nin nya and MM M "M

Oh - MN

SHY not sleep, oh oh oh shcha and:

E and 27 | r M in us

E Mk M M

E o - MN -YNh not sn, o

M and M Ukh hu A and 28 5-47 M M i- nok ny

KE Vinnyi is not MN

And dream

E about

KU g

I A i ro 23 5-47 M M nok ny

IS

OZ ns MN

And dream

IS

Table 5 (continued)

ESBO o o.o

M and M xx

CA

30 5-47 in M 4 nin nya and shshch- ne Mn

And dream

Oh, oh

XM nm" i

M

Uh oh xx

From 1 m r МН ня ны 0-0 М M в Вени не и сн,

Oh oh oh

We are 8

Uh M n 32 i M X same

M--M M M M

E / M o and no

Shchi Shchi sn, o iv) oh

M

Dh N

E M z3 Y xx - -

E M. m "

SHIK not sleep, at 9) OKH 5

M

E in 34 | ru Moh same v

E m. M M pa a tA -- not sleep,

Table 5 (continued)

ESBO Fr

KU and m"? xx

In A and - 35 5-4 M m in nik

IS

OO not MN

And sleep, and sleep. at

M y M xx o A / 36 5-4 M m 4 v nya

IS

-t- not MN

And dream and sleep, about iv) oh

M

E rn 37 | ru Moss I in

E M M M

E 0-Х МН ш-- not сн,

Oh oh

M/Y

З ху зщй дх 38 Мря Маю я я no-Y MM M - yo MN not o

M hu - r 39 o ul Mk What about me

KE tt no

And sleep

Eh!

M vOshOe 5-47 M M She: nok ni

Yv Ryzhiny is not Fr

And sleep

IS

Table 5 (continued)

ESBO o o.o

And your nN

M

1 5-47 M M storage

Yv Ryzhiny

ZK and ! dream

Oh oh oh

M ti nN sn 42 No Y Z mm a z z z z - Z I no no sn. at!

M

Gi et M M She: 43 as nick in the school of MN not about

B

In -i-

Your; with (c) days Mi M Sho nki ny ; not a dream oh oh

M hu -

Osh; 45 o De od, v i ; On

E ne ko sn» o oo

M and your 46 E M - MAH nya ni d- ne MN ns

Table 5 (continued)

ESBO o o.o

And those 47 E M. - Makh ni v

E o - M M d- ns Mn ns o

M louse

M

48 5-47 МЙ ShХ I ny

E and d-ns (v

E sn, o

M your nN

M

43 5-47 M M h niya ny

E sh- b

E ns

E sn, o

M was tearing up

M

5-47 Mem khyanya y d- MN

E ns

E sn, o oo

And so on

M

51 o -G Mch sh a n

E d - MN

E ns

E sn, o

M. of M

N

52 5-47 M m nki v

Yap.

Well, no

E sn,

Table 5 (continued)

ESBO o o.o

AND

Uh M

N

53 o em M M nyk v ; and

Well, no

E sn, o

KU xx right?

N

54 5-47 M M nok w

Yap.

E ns

E sn, o oo

M

N o den M M ni ny ; and

Well, no

E sn, o

M x M

N

56 o em M M we in ; and

Well, no

E sn, o oo

J

Wow GB

N

57 o u M M nn ny; yes

E ns

E sn, o oo

Х и Х | xx

M shkh M ikh 58 5-47 M M - w

What a dream! dream

Table 5 (continued)

ESBO o o.o

M y Ga Uh xx A y ro

M

59 5-4 M M same same

E sn y i sn, o oo

M and | M | Oh

Mem yo M Sh-e o -. well

E sn y i sn, o oo

I and M xx

ХУ А and ХЖЭ

M

61 5-4 M M ni ni

E sn and i sn, is)

M

62 o u MY m and MN i same ; and

Oh, no

M gi

M

63 5-47 M m xx nick v

IS

E -- Oh no Nm

E sn, o

M louse

M

64 5-47 We M xx nok ny

E is n- not NM

E sn,

Table 5 (continued)

ESBO o o.o

M mosha ek MU M Sho: 65 --e leads Z ж -- ny ne m sn, o oo

M

MU - Mach

M M M like water - no, no (0)

M

67 5-47 and MN niya ni

KE ren

Well, no

E sn, o

M vav - xx o dm M M M MN nya no; and

Well, no

ER sn, o oo same

Say M xx u mir 5-47 ve M o - nyky nyky

IS

E - not a dream

E sn,

Table 5 (continued)

ESBO o o.o

M oshe - M u M M y: in ne NM 70 of them ne nki in

M

EE about SN (in; Оу / with ra

Well, you are 71 and | ru M nya nya

R M. M M 0's. -- not sleep, c)

M

- xx 72 5-47 M M Mn no no iy nt.

Well, no

E sn, c)

M

73 5-47 M m eh MN nin v iy ly.

Well, no

E sn, o

M s s xx xx A and -

M

74 and 5-4 M M o ni ny --

Not a dream

E sn, o

M

Sai s xx shhhh A and -

M

75 and 5-4 M Mo ni ni et,

Not a dream

E sn,

Table 5 (continued)

ESCB Sn; about M

E s TI s y; tv |u more What NV NV

M. M M d- not sn, o

M y y

N

77 5-47 m M ny ny

IS

E -- not about

E sn, o oo

KO

2 we scho A and 78 5-47 M mm 4 nick v

By the way,

Well, no

E sleep, o B in M-

M

(in; xx H MN 79 no | r nky in no and MM M no no sleep, (o) sleep,» 9 o

Uh, Gobi and 7

E | AND

R ro sh sh

I Hv M M - not sleep, sleep, oh and

E in SY with y; 81 and R | romance

M M M o-«y.yuЮ1 -- not sleep,

Table 5 (continued)

ESCB about (c)

B

Si - M in MOm Shh u- ne Nm 82 s ne nya ni m

EE o

KI vosha - M uk MOm xx u ne Nm 83 o ne zhe nin m

EE o y h r yours; rya -- 84 o already M M y ni nya

IS . not with

Not Mr

E o y ekh -Ж ru 85 o already se M--k stump in i shcha NIGHT,

And no

E o chi and GT Uh xx " and le M M - sh nya and A

E d- ns

E sn,

Table 5 (continued)

ESCO o m i m i

HU | y and 87 5-47 M M - zh nya

IS

Well, no

E sn, o o

B

2nd St

N

88 5-47 Plural

IS

Uh-sh- no

E sn, b oo

B hu pe Fe

N

- 5-47 M M o nya n

IS

Well, no

E sn, b oo

B xx 5-47 M M We are not

IS

E -- Oh no

E sn, o (v! sn

Ko y eh sh m

M

91 Ezh M Ya nya

M M

Oh no

E - KI dream.

Ki and y: SI Mt

M / 92 Ere Mnki nik

Mem M

Oh no

E sh-- KI sn.

Table 5 (continued)

ESCO o oo and oh M s sy

M

93 5-0 m "lily nin nnn e ne

Well, not from MN

And c) and

ZO

M. a xx 94 and 5-4 M Mo nya nya

Well, no

E sn, c)

Hey, 2nd St

N

- 95 and 5-47 MM of Moscow

E -- Oh no

E sn, o chi 2 and skh

N

M. du y 5-4 M o sh sh

Well, no

E sn, l Z

F --

M M

(v | y: y МН 97 щ х - ния ни 3 no y no no no sn, и Z n -

M M

(in | in: МН р no not M M m no no no no

СН» сн,

Table 5 (continued)

ESBO oo r cSOSO

N

5-47 M M about the lower part of the present

IS

Uh-sh- no

E sn, o and od

N

100 o -iU M m o - 4

IS

Well, no

E dream c) n -

M M o | eh and Mn 101 - nok ni

M M M no no dream. o o o |/ Z y M- (v | y: y МН 102 - niya ny

M M

M no no no SN" c) and vva 103 5-47 MU m and o nki in

IS

Well, no

E sn, c) and 104 o --U kat Zno i -

IS

E -- Oh no

E sn,

Table 5 (continued)

ESCB

(c) (c) Be

Yes

М М ех H Мн 105 М СС nick v - not sn. (c) and with n -

М Эх Н МН 106 m ud nik v - ns sn, (v)

I Be p -

M M xx N MN 107 M SS niya ny - ns sn, o Ko oh g Ehrya y y 108 5-47 M M 4 zh nin

IS

E -- Oh no MN

E sn, about Kt

Sai Ge oh xx g 109 5-47 M M - sun, same day

IS

E -sh- not o is sn, o

B

Uh huh

VO, 110 5-47 MM M M same building

IS

Well, no

E sn,

Table 5 (continued)

ESCB

9) ro

E

Se SI Mt

ХМ / 111 E t M no no

Oh dear M. Z

E 5-0 no sn, o sn 2 and m xx

She" M

KOM in 112 E r M nya nya

E uch M M (v

Y - not a dream, c) a dream! ; 8

Eh and U y; -- 113 E Zh M nok nok

M-- M

E yp- ne sn, (c) y 114 5-47 y M -n-Khy sn, nya nya

IS

E - not MN is sn, (9) B 115 5-47 and M - and sn, ni niya

How - it's a dream,

IS

It fell

M - M 116 5-4 M M -4 i c

IS

E OZ not Mn

E sn,

Table 5 (continued)

ESBO o o.o

B хх ГТ сх - и и 117 5-47 М M 4 ж ния

IS

And OZ is not MN

Ah, sleep, oh!

B eh M heh

At 118 5-47) and Her - I

IS

E -- ns

E dream at! and west M ve

SU

119 5-47) M M in the present day

IS

E --O ns

E dream c) oh i 120 5-47 M m m MN nok ny -- ne et ne

Table 5 (continued)

Compound Max. oh oh

I o T Fe 121 M - х ж ж - М М М МН рый not сн. oh oh

M

/

M r 122 o dol M M M zhny

No, no

E dream

Oh oh oh

Kh

0 M xx what and i

M

123 o shotm M M 4 MN niya v

No wounds

E dream

Oh oh oh

M ra 124 M - MAK nya z - M M d- MN not sleep. oh oh

M your 125 M - Mach - z - y y -- MN not sleep,

Table 5 (continued)

Compound Max. (c) Fr. вх х 0008 / / х- о хх и МН 126 no | no

On M Mem not not sleep, (in) o. вх х 0008 / / х- о ку M МН 127 no | neither nor

Nzo M Mem ne ne sn, (c) Fr. вх х 00005 / / х- о МН 128 re | no matter what

But ns sn, (c) oo sn

M. I

With and 7 Eh len that

M still 129 o dotm M M | nick nick

E -- MN no

E sn,

IS

Table 5 (continued)

Compound Max. oh oh

M

With oh shshchy | Eh

M. d - y M M M M MN y 7 m NI shin Kk) not o oo

M

From ex 7 oh m

M. - M. and M M M 131 c) n.e ni zh -- Y MN kg ne o o o

M

M to what sn 132 o shotm M M M m nn ny

Well, no

Well, no

Oh oh oh

M

With and 7 Uh still | and I

M - 133 o'clock M M disappeared

E d- Me sn,

Oh no dream

IS

Table 5 (continued)

Compound Max. oh oh

J

Uh 7 x

FO, 134 o schotm M M M nya niya

Well, not Vena

E sn,

Oh oh oh

And xx 7 x she still; 135 5-5 M 7 and the same c

Ye yang no

From a dream;

Oh oh oh

J

Uh 7 xx

E

Mom 2 M M. 2 136 5) in same in - MN in not o oo

Ж хх 7 ох -- and Y rya

M

M M M

137 5) no I I -sh- MN no

Table 5 (continued)

Oo oo

M

With and 7 Uh still | and I

M

138 o sho M M 4 nya nya

E "sh- M sn, no

E 37 sm,

Oh oh oh

M

With and M oh still | and I

M

139 o dotm M M 4 vv y - ns en,

E 37 sm,

Oh oh oh

M

With o and FI

N

M - ЩУ сн 140 5-1 М М М МУС но ня

Well, no

E CH,

Oh oh oh

M

WITH

Ex 7 t;

Mu. - M--M

M M M

141 5-5. lilia slia ry not sleep, 6bo

Table 5 (continued)

Compound Max. oh oh

M

Eh M y

N

M... - x 142 o house M M M nya v

Well, no

E sn,

Oh oh oh

M

From the 7th

AND

M d- Mach 143 o OM M M nya nok

Well, no

E sn,

Oh oh oh

J

Uh 7

N | x sn,

M - M--M 144 o OM M M nok c

E -6- no

E sn,

IS

(c) (c)

M -t--

HER i n oon 145 | ru in we are not M Y

WITH

НЕ сн, ns SHHI

CI

Table 5 (continued)

Compound Max. (c) (c) at "9 h

M t

HER IN: n tone 146 | ru nia v ns and M. Y

With no sleep, no sleep

KI o oo

M and 7 ex

OO

M. chi M y 147 o shom M M zh ni

E sh-7 (c) no

E sn,

IS

(c) oo sn,

M and 7 Uh still | and Y ro

M

148 o -. M M I I

E - MN no

E sn,

IS

(c) oo sn,

M y 7 Uh s | and I

M

149 5-1 M M 4 niya v

E - MN no

E sn,

IS

6b2

Table 5 (continued)

Compound Max. oh oh

AND

-x M. Kh

I. Su

M and 150 o dotm M M m we same

E "- no

E sn,

Oh oh oh

J

Eh M H

IN seams:

M

151 o dotm M M m niya ni

No, no

E dream

Oh oh oh

M where 7 in; er poppy

Mu KU 7 152 o sho M Mo ni nya

No, no

E dream

Oh oh oh

F xx 7 ru

Mu. - -M 153 (c) M, M "nya nya ryy ne sn,

Table 5 (continued)

Compound Max. oh oh

J

Uh 7 ru

M. - -k

M M M

154 5-5) odken ny nik ryy sn. oh oh

M and 7

Gu

Mo ikh -kKkM

M M

155 5-5) where he is not sleeping now,

IS

Ee o o o

M

Ex 7 Ex

WHERE)

M shotm М M 4 156 o p y nik nya - from 9 Mn o ne Su

Table 5 (continued)

Compound Max. oh oh

J

Whoah 7 oh

E | H 157 M r. M 2 niya ny and schotm M M

E (c) - h chn not Su

Oh oh

E I eh M y

E I (c) | H 158 2 MAX v v is) M M M

MN is not a dream. oh oh

M

WITH

E t M Uh m 159 E M... d M. ih i h i ee; Well, not me Kk MN not SU o oo

AND

ЕЙ: M Ukh m 160 E M - M 2 niks niks and Im Ж not pcs, Z МН not -/ (9)

M

5, | and M fo 161 E ru M niya ni i - g shk z n ne

Table 5 (continued)

ESCO shinnnIshIIIinnInIIjjjjjjiInpPppPIPIPIPIIinIinIninIninInnI V LIA o

M xx M 5

M - y y NO - 162 - not I Mn I I o not Su o

KU mech

M - y y uh - 163 - I'm not MN nanny, oh no Su o oo

KhM and r t

M- 164 5-47) B du. g

KE M iiiniy sn,

IS

(in)

M r

M still Mi sleep,

IS

RE

(in)

M

Sai Ge po

M --M 166 5-47 M odu, the same

E dream shi:

Table 5 (continued)

ESBO o o.o

ХА y r t 167 o M Mav o v v ; On

It's not a dream.

Huh huh? c) In the 19th century n / 168 not in M o M | nya nya

M M I don't Hu don't sleep, oh oh

M 2 (0) A m

A 4 and 169 M M a M. | I'm not HM in n.s sn, not sn, o oo not sn, X not o | St. M 7th 170 o - MAH nki nya

M M M

(in)

MN

Vodi sn, o oo ns sn, X ne o | 5 M and 171 Z - Mach, in niya

M M M

(in)

MN

Vodi sn, Fr

I and Ovshcha 172 and E Z 2 Makh nya nya

M M M o sn,

Table 5 (continued)

ESBO o o.o

M i Ov shcha 173 J E 2 MAX v ni o M M M ne MN sn, o o / x 2-8

MN

174 ES m m- i v niya

E not sleep, o o / x

IN

MN

175 ES mme i vnya

Well, not a dream, in!

M xx -F t i What sun, o (6) NKY / VC

IN

M o | xx N M- 177 M - Mch nok ny

M oda not sleep, o (c) o / x

Ve o | хи м- 178 - ш в н

M M some do not sleep,

Table 5 (continued)

ESBO o o.o

M o oh M y 179 Z - Makh zh nya o M M M lodi ne sn, o o o

M o oh M y 180 Z - Ma ni z o M M M lodi ne sn, o oo

E M

--k r and 5 U

E і- M-- 181 mm de nok not sleep, o

E M hu r

E o | m In 182 th - M--ki ni niya

M M M don't go to sleep, oh oh

E M

- to r

E o | m U

Hey Shan! (c) not sn, o oo

And and about | y: m U 184 2 M--ki sh zh ns M M M pyo ne

With no sleep,

Table 5 (continued)

ESBO o o.o

M

8 and M

M M M

185 Ki nin nya no no MN sn. not a dream, a dream oh oh

M

In oso and What a dream. oh oh

M

In sOoSo 187 HER " du in the same and What sn. o oo

M с M сх хх | y i o ul M M 4 188 xx. oh nyah nya not "he sn. at

M is yours

M and Mach 189 0-І M s M nin nya still 7 not MS

With o o o

Y i vosha 190 E M ro ma nk nya

E 5-4 Mne M and dsh- ne - 7

Table 5 (continued)

ESBO o o.o

E M vk r

E o | m U 191 and Z - Med nok ny

M M M o

Water sn, o oo

E and ek r

E o | m In the 192nd KO - Mem v ni

M M M o ne de sn, o

M

St - M 193 X, M M x ni ni ni otsi U ne ch ne? sn, SN" not o

M vOshae

Mu - Ma 194 ІИ и г; nya z y t Su ne sn, o

M louse

M - Ma and Y Y not sleep, oh

M and hshchy | h

Mu K- M 2 196 HER M Y (c) ny nya and not Sun sn,

Table 5 (continued)

ESBO o o.o

M and HT scheme

Mk ve M 0-X 197 i- 4 o not - in sn, e)

B with M

GO memes m M Shk 198 -. water Nv Nv no no no sleep, sleep. sleep, o.o

ХМ сн, y р р ще M о лк М M Ш 199 -7 nki in ne сн,

E E

IS

(c) oo

HM at Ukh 7 and 200 HM. rya and Ma

M mi Yur nya w

M (6) or C is not a dream, (c)

B dream p

M-- xx Mom -- not me,

Table 5 (continued)

ESCB

(in)

M sn, y

M-- zhk and M M 202 i-( nki in ns o sn.

Oh yours

MM M M She: 203 g vl dya, no no

Oh and hurry

Mk 4 m MAX / y achan k y SHISHY not o

B y hi - M 205 sho M M Z nin v

Is it not MN and dream.

Oh oh oh

M

M- dm m M M 206 cheek I-4 ne nya in sn, ns sn. dream

Table 5 (continued)

ESBO o M s g m 7 uk E M What; 207 "- well, it's not a dream. It's not a dream, c)

M

The same mch and

M. -- MAH 208 sne o M M zhnyah not - not MN

Well, no

EE person o m i / --

M M zhu N MN 209 of them | nki in

Not Ж M m SN. not M

With /7 M not not SN, oo (c) mi / ---

M M same as MN 210 and | nok ni ne M Mn sn» ne M

Z-/7 M ne ns SN» o o

M

- and

IN

Hm. rya MAX 211 ki M M i v ne MN

What a dream

BE Fr

M is yours

M 2 MAX 212 o-(Х0 M y v n

Well, no, no

Well, no

E SN" no

Table 5 (continued)

ESCB

(c) GF) Fr

M

I M i 213 r M M ni nya

M sn, oo o U / -

M M o eh N Mn 214 ДЖ - hundred I same

M M M M sn,

IS

E c)

M r

M

215 What m we m 4 nya in e-/ hi ne mn ne sn, sn, o

M r ho M 216 pe m M M 4 j j e-/ hi no Mn no sn, sn, o

B

Ha what

M M M M

217 study, don't MN, don't sleep, don't sleep,

Table 5 (continued)

ESCB

(F) HF) Ge)

M

M

218 not ХХ in 4 - - -/ хи not МН not сн, сн. at!

B a M 219 ns X M m 4 zh nin - hi ne MN ne sn, sn. at

KU s m oh sn, | y Ts 220 No -4 ve m -d j zh no -- no MN sn SN» o oo

M

- Zh

Higher education;

M... - M-m

E d- with 7 not sn

EE sn, 7 (c) GF) Ge)

M

From those 222 Sh M M MAK nin liny sn. oh oh

M

S" ti 223 sn, r 4 M Z v ni ne wl A ne MN

E Z

EE SN

Table 5 (continued)

ESBO about about

M sn, | ох з и г24 при самих з з

But MN is not

IS

Iv) oh oh oh oh

AND

225 E M M M Moh in the same

M

E sn, z ne sn, o o

M

To AJ

Ge) SHIK M- 226 is not MS M nor is it sn, oh

M y and M | oh sn, 227 Ne - ve m We don't -- not MN sn, SN» o

M r "ti 228 Kho si Mokh v w

M sn, Fr

B

- t "gi 229 ХХ се Mokh v v

M sn,

Table 5 (continued)

ESCB

M o oh y y gi 230 M 2 M xx nya v

M sn, oo (c) KU /V xx M t

Shchi y y Mn ny y y M M t

НЕ сн, хх

Y U We MN cancer (o; eh gvaK X se o 4 4

Y r ara Mat ne M / ne ne o y M xx 7 y y | H 233 and m. - Mach NV Nv o- M M m she a ne o y KI eh aa

And | and 234 and Mo. r Ma i v o- M M m va i no o

E M xx GB y y | H 235 E M. -May 5. nin v o- M M M she ey no

Table 5 (continued)

ESBO o o.o

And louse

M

236 E and -2 M m what is nya - d- not Mn

E sn, o

E dream M sn, Ge) eh M y

And | H 237 E Z 2 Mach vv z o M M M i sn, o

M r is not yours - M 238 - mm m oz v nin ne -shsh- ne "he sn, SN" o

And those ra - MaAZ

M M M M

239 or od! but now

from sleep

IS

EE oo o U / -

M M

240 o hundred in in and In not sleep. oo in

M M- o | сх и МН 241 ше, M sto in the same and U ne сн,

Table 5 (continued)

ESBO oo (in) me and / -

M M o z shchi MN 242 EE | z vrya M Mn not sn, oo (in) me / -

M M o hu shchi MN 243 Re | well, rya shk not sn, oo in shi;

M M- o xx H MN 244 | I am in

TO, he YOU in not a dream. oo in shi;

M M- o xx H MN 245 | same in

TO, he YOU in not a dream. о, о (c) У / -

M M hun Mn 246 their du nok ny - not and M M not and nis not sleep, oh, oh oh and

M M-- hu n MN 247 0. | hundred in in - not o M M M not and nose not sleep,

Table 5 (continued)

ESBO o o.o

Y eh M y sn. | H 248 No 0 M M oh I'm not d- not "in sleep, SN," o oo

AND

5

DH My dream | H 249 NIS -0 is still in vv ne dsh- ne su sn, SN,» o o o

A louse

M - M 250 7 M M with v v dsch- ns MN ns o

M louse

M - M 251 7 M M i: g zh d- not MN not o

M vrOshae 2gnogn M y Moyu 252 o- M m M v ny d- No MN no o o o

M vrOshae

Mrya Ma 253 gn o- M m M nin v d- Nis MN ne

Table 5 (continued)

ESBO o o.o

M

Ukh Y 2-7 254 M. - m | g z 5-47 M M on dsch- ne MN sn, o

M va | 2 more

IS

255 t 5-0 sa Mokh on nki in -t3- not MN sn, o oo

M

From vk M to

AND

256 M - MAX I am

Sho M M "-6- not MN sn, o oo

M vrOshae no M - Mach 257 she M M v nin d- ne MN sn, o

M vrOshae (o) M 2 Mach 258 seh M M zh zh d- ne MN sn, c)

M

GT and your 259 cheeks o dm pav skh in same lv in not other

IS

in a dream

Table 5 (continued)

ESCB no

Oh

Go) (6) ия и: m МН 260 | more about them

MM We M a - no no

And it's not

E | -k

Ge) (6) and r 261 | A: her M, MN h h mm shcha M 5-5 ш--еО--- no no o o

M eh m? y and 262 y E o Ul M M SHE: i v

E and not "y sn, o o u xx m y

Dy 263 M - in the same

Oh and oh M M

E y- ne MN sn, (in o

B on sh "7 | y5

N

264 m... r Mikhny v

In M m 5-0 MN -- no no

Table 5 (continued)

ESBO about about

He has a louse of 265 E mm, and Moss is in no no o

Y M un - r 266 y 5-4 M m MN zh nin y 8-7 no no c)

Y M mun y ve M, 267 y o Y ME rukl same is in

Not at 5)

B

E o and | and | She 268 and o sh She nky nya

E | M M M

MN

ЖхЗ not is not) o mi dO m? | She

NN 269 Mem schy M is 4 nanny niyinny I MN -8-O no

E 2

TU well N sn, o o

B non dO | Tsh | oh 270 V M AKZH M. and in the same vada, pi: - K-t not about MN

M i and r 5; in,

And you don't sleep,

Table 5 (continued)

ESCO o ом/ЙЙ х --

With and r

Huh

And no

E and sleep, at -0Y

Come on

Ex 7 " 273 m what but I in

It's not a dream

E E with c) c)

Ki xx m? and: no

M... d M ikh

In M. M

274 - code in the -th- -th races about -6eY

Kk - pk: 275 p which in I ; in "

NE sn, at -6eY

Kk - pk: 276 I and - ks with the same

E -- in "

NE sn, at -6eY

Kk - pk: 277 Ge) uk ns ne - ; va in "not sleep,

Table 5 (continued)

ESCB at -6eIh

Kk -shchi

Gr 278 M - Nnya nya vla 7 M

I am

E E Not sleep, about tt

Kt -

Gr 279 M r N nyan nyah

Well, I-

E E Not sleep, not M their o; and: kak (9) 280 M 2 and the same nin

E CH, 5 M and in SN, M SN, SN, not M

Yi Fo;

Эх их 281 m. что но я в г сн, 5 M яЕе

E sn, and St

M

(c) with | m rt sn h8h mm - no no nya in sn, 5-5 M --i- --O mos,

Well sleep, with in! at

M and m"? M"

M. ХХ, 283 ше о-й.17 " And in the same - not MN sn.

IS

EE

Table 5 (continued)

ESBO o o.o

M

Mem By She 284 no 9-7 Y In same in rea not sn,

IS

BE

M to h o M

With a width of 285 | r ni nin

M M me: 5-4 sn, yav sk h sn,

M t h

M her m 5. ul tm ev,

M

286 | r we in

Мк M ше 5-0 сн, --- --4 M сн, g сн, о о

Ko hu p y

N MI

287 B Mem Men i in dO not

E sn vd gn 2n z ne Сh (v) o Y z mu, 288 SHI z -

Mem M

КО сн» 5-4 сн, -- yo M сн, g сн, not Сх 9 о, Й z 7 289 | in " nki in

MM M

KO sn» 5-4 men, --- with sn. g sn,

Table 5 (continued)

ESBO about M

BYA n-

Ho I I 290 | nya nya

M r -k M in sn, 5-K men, -- sn,

I'm in a dream, not M tech

M вх я х 291 | come on

M r -m M in sn, 5-4 men, - sn, -e g sn, c) o

B

FI Iv

Swing

Me. - 292 5-47) M dl zh in -i- r.s

LONG LIVE St.

BE o o

B

I am IF

Mach no M - 293 5-4 m and MN in the same dO not sleep, o o

B

I am IF

Mach no M. - 294 5-4 m t Mn v v dO ne sn, (9) (c)

B hu t y

DI

M. - х m М М 295 5-4 nm ni zh dO ne

Well, no

IS

Table 5 (continued)

ESCB

(c) o o

B hu t y

DI:

M. - x / М М М 296 5-4 nm same to no

KE not but

IS

(9) (c)

M hu t y

DI:

M. - Сх / М М М 297 5-4 nm same same dO no

And not but

IS

(in)

M

298 M - mech ?n ni ni zn UM M M zn 5-4 NM I do not sleep, 19) (c)

M

Still Kt 299 zn 5-4 m No Nv Nv drosh no g2N no o

M

00 M. - Mk ?n zh ni (in nm to ne sn, (in)

M z hu "7th gn | N u

З01 M - B: ?n zh ni 2n y M M M with 5-4 NM to no sn,

Table 5 (continued)

Let's get together Molecule | Max. activity of I(ESBOs) (c)

M

In -

Gu

302 uk m M shk i them

And 5-4 or

Well, no

E sn, (c) o o x/ hu m y

H in 303 (c) - XX in NN

M M

NM not sleep, (c) from 9 / / x tod:

Honey 2 ml

Z04 2-4 niyinny i and shk with R sn, (in) 9 o / h

IN

OS

Med 2 M y 305 2-4 4 y o sho with R sn, (c) hey y -

So Chi

Med 4 M I" 306 5-0 nin I o sho

E sn,

Table 5 (continued)

ESCB

(c) ge) KU re: oh M - -

M-- M M 307 5-0. I put myself in what

E sn, (c) ge) KU re: -

M-- M M 308 5-4 code I and 144 and sho

E sn, (c) o) o // / X re: cha E m MN 309 5-4 nin v o sho

E sn,

Other implementation options

The foregoing discussion discloses and describes only exemplary embodiments of this disclosure. One skilled in the art will readily appreciate from such discussion and the accompanying drawings and claims that various changes, modifications, and variations may be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims (46)

FORMULA OF THE INVENTION 1. Compound of formula (1): o Kf (va Z 1 y KE ) t N M Z 7 Kk s Z (ha y ; (1) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - ring A is a phenyl, 5-membered heteroaryl ring or b-membered heteroaryl ring; - ring B is a pyridinyl ring; - ring OO is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X is 0, MH or M(C1-Cdalkyl); - every Ki! independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached form a 5-6-membered cycloalkyl or a heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups and C1-C2haloalkyl groups; where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl group, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr -groups where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2haloalkyl groups, C1-Calkyl groups, hydroxyl groups, C1-C2alkyl groups and C1 -C2haloalkyl groups, and - each Kb is independently selected from hydrogen and C1-C2alkyl groups. 2. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of formula (I) is a compound of formula (1I-A) or (1I-B): o Х / в2 З 1 ( in m v t N M v C zh 2 (va v (PI-A) or o Zx / 2 Z 1 (va a v ) t N M- 2 AZOV 4 v3 or (od , (P-B) its pharmaceutically acceptable a salt, or a deuterated derivative of any of the above, where: - the carbon labeled " has 5-stereochemistry or K-stereochemistry; - ring A is phenyl, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - a ring B is a pyridinyl ring; - ring OO is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each CI! is independently selected from C1 -C2alkyl groups, C1-Chaloxyl groups, C1-Cghaloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, a hydroxyl group, an oxo group, a cyano group and -(M)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached form a 5-6-membered cycloalkyl or a heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups and C1-C2haloalkyl groups, where: - K is 0, 1, 2 , 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; Zo - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; - 7 is a bivalent linker of the formula (MG, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr- groups, where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and MKU is independently selected from hydrogen, halogens, C1-C2alkyl groups, C1-C2haloalkyl groups, hydroxyl group, C1-C2alkyl groups and (C1 - C2haloalkyl groups, and - each Kb is independently selected from hydrogen and C1-C2alkyl groups. 3. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of formula (I) is a compound of formula (PI-A) or (PI-B): о оо (В2)е У 1 о а в ) t N M M в Сх 7 во Z (ka в (PI-A) or о оо (vu У 1 She cha в ) t Н M M---я 7 в C (from and: ,(Ш-В) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - carbon marked "has 5-stereochemistry or K-stereochemistry; - ring A is phenyl, 5 -membered heteroaryl ring or b-membered heteroaryl ring; - ring B is a pyridinyl ring; - ring O is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b -membered heteroaryl ring; - each Ki! is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0 , 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B7-groups or optionally two K4 together with the atoms to which they are attached form a 5-6-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl ZO groups and C3-5 cycloalkyl groups, or 5 and 6 on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C82 alkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C1Ocycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of the formula (r, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr-groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl, C1-C2alkyl groups and C1-C2haloalkyl groups, and - each Kb is independently selected from hydrogen and C1-Sgalkyl groups. 4. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of formula (I) is a compound of formula (IM-A): m M visi" 2 4 Z (code Kk MA) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked " has 5-stereochemistry or K-stereochemistry; - ring O is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - each Ki! is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups , halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each short circuit is is methyl; - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached form a 5-6-membered cycloalkyl or a heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups, where: - K is 0, 1, 2 , 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or 5 and 6 on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-Cgalkyl groups, C1-Cghaloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C82 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of the formula (g, where: - g is 3, 4 or 5; - each Y is independently selected from C(H8)(H9Z)-groups, -O- and -MABr-groups, where the heteroatom in 7 not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl group, C1-C2haloxy groups and C1-C2haloalkyl groups, and - each KO is independently selected from hydrogen and C1-Sgalkyl groups. 5. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of the formula (I) is a compound of the formula (IM-B): o o o (vu U o --ek - M -E M , M Kk s r; Ochi 4 3 (td v (svevU) ve (mV) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry - ring OO is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each Ki! is independently selected from C1-C82 alkyl groups, C1 -C2-alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached form a 5-6-Zo membered cycloalkyl or a heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups and C1-C2haloalkyl groups, where: - K is 0.1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl group, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl group, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Kb is independently selected from hydrogen and C1-Chalalkyl groups. 6. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of the formula (I) is a compound of the formula (IM-C): - X M M ach, v Kk v Ox Z 8ro b Kk (svv) v (o) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K- stereochemistry; - each CI! is independently selected from C1-C2alkyl groups, C1-C2haloxyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkoxy groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with atoms , to which they are attached, form a 5-6-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-C6hydroxyl groups and C1 -C2haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl ZO groups and C3-5 cycloalkyl groups, or 5 and 6 on the same carbon atom together form a C3-5 cycloalkyl group or oxo; - each of K5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-C82 alkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl group, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Kb is independently selected from hydrogen and C1-Chalalkyl groups. 7. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of formula (I) is a compound of formula (М-А): o o o (vu U 07 - Mod M that 3 si» 7 4 Z its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - carbon marked "has 5-stereochemistry or K-stereochemistry; - ring OO represents a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a b-membered heteroaryl ring; - each Ki! is independently selected from C1-C82alkyl groups, C1-C82alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, 3 or 4; - each K2 is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups , C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached, y form a 5- to 6-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-Calkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups and C1-C2haloalkyl groups, where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl group, C1-2Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of the formula (r, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr-groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl group, C1-C2haloxyl groups and C1-C2haloalkyl groups, and - each Kb is independently selected from hydrogen and C1-Sgalkyl groups. 8. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of formula (I) is a compound of formula (M-B): o o o (ya U Shi what; M s Shk M what cha (ka vi (svev"), ; (U-V) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - carbon marked ", has 5-stereochemistry or K-stereochemistry; - ring OO is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - each Ki! independently selected from C1-C2 alkyl groups, C1-C2 alkoxy groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1- C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo groups , a hydroxyl group, a cyano group and -(U)K- В?7-groups, or optionally two K4 together with atoms to which they are attached to form a 5- to 6-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-Chalalkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups, and C1-C2haloalkyl groups , where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl group, C1-2Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - r equals 3, 4 or 5; and - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl groups, C1-C2haloxy groups and C1-C2haloalkyl groups. 9. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of formula (I) is a compound of formula (MI-A) or (MI-B): o oo (v2)e U -1 ur!1 I-i yah M XX M v x 7 v Z (t) Kk (MI-A) or o oo (v2u U o, 7 s 1 --ek M Kho M C is a pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - the OO ring is a phenyl ring, a 5-membered heterocyclyl ring , a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - each Ki! is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, a cyano group and a hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, a cyano group and a hydroxyl group ; - n is 0, 1 or 2; - each KZ is a methyl; - each K4 is independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7 groups , or optionally two K4, together with the atoms to which they are attached, form a 5-6-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups , a hydroxyl group, C1-C2alkyl groups and C1-C2haloalkyl groups, where: - K is 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl group, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens; - 4 equals 1 or 2; - 7 is a bivalent linker of the formula (r, where: - r is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr-groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl group, C1-C2haloxyl groups and C1-C2haloalkyl groups, and - each Kb is independently selected from hydrogen and C1-Sgalkyl groups. 10. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the compound of the formula (I) is a compound of the formula (MI-C) or (MI-0): о оо (ву У 1 ( in 4 XX M VZ sii, /, (vu) v3 vdo h (SK), (MI-S) or o oo (v2u U a 7 s 1 I --ya 4 4 M Ach 829 (v) vi (sveveu, ; (MI-6) its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - the carbon marked "has 5-stereochemistry or K-stereochemistry; - the OO ring is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered heteroaryl ring; - each KI! is independently selected from C1-C2 alkyl groups, C1-C6 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, a cyano group and a hydroxyl group; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2alkyl groups, C1-C2alkyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, ha logons, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached form a 5-6-membered cycloalkyl or a heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups and C1-C2haloalkyl groups, where: - K is 0, 1, 2 , 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C1Ocycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups and halogens; - 4 equals 1 or 2; - r is equal to C or 4; and - each K8 and KU is independently selected from hydrogen, halogens, C1-C2alkyl groups, hydroxyl groups, C1-C2haloxy groups and C1-C2haloalkyl groups. 11. The compound according to any of claims 1-3, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where ring A is a phenyl ring, pyridyl ring or pyrazolyl ring, where ring A is optionally substituted (K1 )t. 12. The compound according to any of claims 1-11, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K1 is independently selected from deuterium, C1-Chalalkyl groups and hydroxyl group, and t is 0 or 1. 13. The compound according to any of claims 1-11, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where n is 0. 14. The compound according to any of claims 1-5 and 7-10, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the ХО ring is a 5-membered heteroaryl ring, substituted (Ka. 15. The compound according to claim 1, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where ring O is a phenyl ring, pyridinyl ring, pyrazolyl ring, imidazolidinone ring, pyrrolidinone ring or pyridinone ring, where ring O is substituted (K2 )and. 16. The compound according to claim 1 or claim 5, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the O ring is a pyrazolyl ring or a pyridinone ring, where the O ring is substituted with KA. 17. The compound according to any of claims 3-5 and 7-10, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the Y ring is a pyrazolyl ring, where the O ring is substituted by (К4)а4. 18. The compound according to any of claims 1-5 and 7-10, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the ring Y is о, и А, м" я, У М 3 2 - / Х х Х -e (В (я (В (da Х хой У 4 | 4 (Ва or Аа) where p indicates the point of joining of the O ring to the B ring. 19. The compound according to claim 18, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the O ring is MA - where p indicates the point of attachment of the O ring to the B ring. 20. The compound according to any of claims 1-19, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or groups - SYUK-K, where: - K equals 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(E5)X(P6)-groups, -O- and -MVa-groups, where the heteroatom in -(U)К-К7 is not bonded to another heteroatom in -ГУ)К-К7 and where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1-Sdalkyl groups and C3-5cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5cycloalkyl group; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C10 cycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2 haloalkyl groups and halogens. 21. The compound according to any of claims 1-19, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from the oxo group or groups -О- СЮК-К, where: - К is equal to 0, 1, 2, 3, 4 or 5; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not Zo bonded to another heteroatom in -(У)К- K?7 and where: - each K5 and Kb is independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1-C alkyl groups and C3-5cycloalkyl groups, or K5 and Kb on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl group, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 is selected from hydrogen, halogens, cyano group and C3-C1Ocycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups and halogens. 22. The compound according to any of claims 1-21, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each K4 is independently selected from: DY life tm vyh howling, half glass ry I Touched them sbfrt-tchu ears in eyes o0onbbitichu ro reve rana mno du dy r avdocho ozh: di things De De" Do Drsya ah tu rya o o v I , where re indicates the point of attachment of the spacecraft to the ring 0. 23. A compound according to any of claims 1-22, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where K is 3, 4, 5 or 6. 24. The compound according to any of claims 1-23, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 4 equals 1. 25. The compound according to any of claims 1-24, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 2 is a divalent linker of the formula (MG, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr-groups, where the heteroatom in 7 is not bonded to another heteroatom in 2 and where: - each K8 and KU is independently selected from hydrogen and deuterium and - each Kb is independently selected from hydrogen and C1-C82 alkyl groups. 26. The compound according to any of claims 1-24, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a divalent linker of the formula (MG, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups and -MAB-groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, and: - each K8 and KU is independently selected from hydrogen and deuterium; and - each KO is independently selected from hydrogen and methyl. 27. The compound according to any of claims 1-24, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a divalent linker of the formula (MG, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups and -MAB-groups, where the heteroatom in 7 is not bonded to another heteroatom in 7 and where: - each K8 and KU is independently selected from hydrogen and deuterium; and - each КБ is hydrogen 28. The compound according to any of claims 1-24, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where 7 is a divalent linker of the formula (MG, where: - g is 3, 4 or 5; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr-groups, where the heteroatom in 7 is not bonded to another heteroatom in 2, where: - each E8 and K9 is hydrogen; and - each Kb is independently selected from hydrogen and C1-Chalalkyl groups. 29. The compound according to any one of claims 1-28, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where each KZ independently represents an ASSOCIATION. 30. The compound according to claim 5 or 6, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - d is equal to C or 4; - each K8 and KU is independently selected from hydrogen and deuterium; and - each Kb is independently selected from hydrogen and C1-Chalalkyl groups. 31. The compound according to claim 5 or 6, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - r is equal to C or 4; - each K8 and KU is independently selected from hydrogen and deuterium; and - each Kb is hydrogen. 32. The compound according to claim 6, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - g is C or 4 or 5; and - each K8 and KU is independently selected from hydrogen and deuterium. 33. The compound according to claim 6, its pharmaceutically acceptable salt or deuterated derivative of any of the above, where: - d is equal to C or 4; and - each K8 and E9 is hydrogen. 34. A compound selected from: 2 oo Я Z Н Н ro M d M --/ ш- МН --/ ш- МН Compound 1 Compound 2 О oo М -- mot M. 4 М. 2 --/ шщ- МН 0-5 М M d- МН EzС enantiomer 2 Compound 4 Compound Z o or o or or 5 m eh oh m"? 5 no | no M. - Ma M. 2 M. ah 0-27 МОМ 0-5 7 MM d- МН d- МН EzS EzS Compound 5 Compound 6 o to X chu U m"? chx m"? N | N Mem m (is) ly m t 0o-i in TSI va Y EzS EzS Compound 7 Compound 8 po bo Н n 9-0 MM She 9-0 M m Mo EzS EzS Compound 9 Compound 10 p oo oo M. - Well M. M. - d M. 0 - - M. d- MN EzS EzS Compound 11 Compound 12 bo ooo sx m"? 5th m"? y m. MAK Nm mmM AN mya dsch- S ln d- MN EZS EZS Compound 13 Compound 14 bor i Z n r M. 2 M. 2 M Mem m M M M 0-7 M Z a a MN MN EzS EzS Compound 15 Compound 16 9 chu o yuue, H n 7 M. 4 M. ah M. 2 M sly Sha 0-5 TM what pad a EZS EZS Compound 17 Compound 18 o oo o Chu n ; Nn M. - M M. 4 M. ah o-9y M M M o-y MM A i MN EzS EzS Compound 19 Compound 20 2 o poyu i! and! sh 2 M sh 2 M 9-0 M cm y 9-7 M cm y EZS Ezs Compound 21 Compound 22 7 9 o oyu She: m"? M. сх m"? x M 4 d -d M | 2 N M y d- MN - Mn sia sich Compound 23 Compound 24 o oo o oo N n 9-0 M cm 4 9-0 M cm i d- Mn - chn EZS EzS Compound 25 Compound 26 o Chui o o, / X zhi M xx ra M | n u r is IN ok- EzS Ezs Compound 27 Compound 28 o om o oy ,7 U 7 xx vok щ- NM vo щ- НЙ Compound 29 Compound 30 o Chu o Chu y 7 Ex y 7 M ss MM ss 7 a d- a vod v v Compound 31 Compound 32 9 chu o ore; y M Сх хх m" s N | | N shk TI She OM ge 0-7 М ЕЗС Езs Compound 33 Compound 34 ooo Ge) Fo ha v- z zv M | 2 N m MN M | 2 X M MN o-4 MTM M o-54 MTMO y y vad y vad Compound 35 Compound 36 9 chu o oo / Their name ;Z "DA rom - M.M M We M | ru N M 0-7 and MN Kk and yoI0: she dl EzS sh- Compound 37 Compound 38 o o, because a and you pakh Н M-M | N zhk M t o-MM mm y 0-7 E EzS E Compound 39 Compound 40 (c) Ge) duya Od ZM Zk v ana M So N My M se Ni - iy MN - MN EzS Compound 41 Compound 42 o oo o 9.0 M xx uva a I V n M-m (o) li kavi ge in a (c) and Z in ; o E E c 43 enantiomer 1 poluka Compound 44 009 oo0o Bu zh (550) s M fakh priro M Ж o Nm d- -8- МН E Compound 45 Compound 46 9 9, o 9 сх m"? 7 сх m"? Me No | NO to live and me p author M. And another school 75 in Compound 47 Compound 48 and ZU ooo and M вх хх m? sia id | | NEO .II ше а на ЧИ о- MM -хй /й о и (c) Ки М МН ЕзС ЕЗС Compound 49 Compound 50 9 че о о й: м"? вх х м"? M | r N I r M | Н M ш- - МН s ЧИ в Compound 51 Compound 52 (c) Chu ooo and M s m"? n | Н Compound 53 Compound 54 (e) o oo Chu Chh m? ху M M ID n m (| n в в Compound 55 Compound 56 сх M ху М N | Н M- Mem M m Mem M МN шк шк вад в во Compound 57 Compound 58 (o) oo bo B ma; ho a, M | - du M M | r N M- x MN their MN o-7 5 M M M 0-5 7 M to still Kk A Bad sh 7 Compound 59 Compound 60 o 0.9 ooo ze u o Se ov - M cm MH 9-0 M cm MU MH 0-7 sh Kk - vad not k- med, Compound 61 Compound 62 o ch o Chu SOS SO M. 2 M. a M. Sa M. 2 2-7 MM 2-57 MOM EzS EZS Compound 63 Compound 64 o o, o o, vF7 yd7 uashe СОСо Н Н 0-7 M ж- 0-0 M zm- x M a Ol what is Compound 65 Compound 66 o oo o o "xx m"? 5 With m y: mM F no, m M F no 0-5 M ved 0-5 M Du Compound 67 Compound 68 o oo B y m? x 5 M xx M 2 N IL - M | - N M - 0-5 M M Ge) and "MM M d- "Lin - nm Ezs she o Compound 69 Compound 70 o chu o 9.5 y M sa i m"? and well m | but o M o MM cm M" mn what he EZS EZS Compound 71 Compound 72 Her 9y; Z /atso sob zh В "7 M mn de p avt - o-i 0-7 |c) de med A Sn Ezo EZS Compound 73 Compound 74 ооо ооо м? Compound 77 Compound 78 o (9 DZ x y sryeo KOS O MO Me 0-0 she M MN d- t, vach li Compound 79 Compound 80 o oo o chu / ro M 9-0 M M Am m -4 -- у- NM EzS s 81 zo y poluka Splukka 82 o chu o zrya M Mu li a pa y 0-0 nak a svi nm 3 - IA EzS o E TYA Y chu M. rya MU M. r. M u 0-42 MTMO M play M K po shnod da E EzS E Compound 85 Compound 86 o du? o oo y5 M y s m"? M 2 Nm ud M | 2 N v v o 9, o oo Ho m"? We are M | - N M | 8 d | - Compound 89 Compound 90 o o o o, Z - y m X M xx m? H M M | and du M M | ry du M MTM m MM kita k-t sa Sa E E Compound 91 Compound 92 o chu o oo lai leeo o- mts ai o- t Myh smcho de Mn -- EZS EZS Compound 93 Compound 94 o o o 9, 7x m with m? M | - d M | ru n Compound 95 Compound 96 o oo o chu S M MM cm - MM cm 4 MN MN Compound 97 Compound 98 o odu) o 9 Mem M k kol yak k o e-a S a ws K7 vd even 7 Compound 99 Compound 100 (c) Chu Ge! is) o - M" eh Ge! de o, KA ky she M We OM Compound 102 Compound 101 ooo ooo "xx m? sx sx m? "хх no || | no dy m Mbso o-0 M sm ke; 9-5 od K rutin ne mod Compound 103 Compound 104 (c) (c) - 9 - M she M 5 Compound 105 Compound 106 o oo o 9 , - 8 and i: share: at-. 2 | M in M | - N M - va, mm Me 0-5 MmOsMm MN to MN EzS Compound 107 Compound 108 oyu shk M. - M. ah M. 2. M o-44DC1M M M o--y M M M where is the water! de EzS Ezs Compound 109 Compound 110 o chu bo She M ih oh m"? ih I | vn J m | nm Mem vi M Mom M o Y. om vach v Compound 111 Compound 112 ooo i nu sta Du powder Kk re - A le EzS Compound 113 Compound 114 ooo M uva A M sce N M - i she a MY me 0-5 Mt va MN - MN EZS Compound 115 Compound 116 ooo bo n N Her M. - M. 2 M.. i- M o--4 MTM OM 9-5 TM and water that EZS Ezs Compound 117 Compound 118 TT. Hear (c) oo y M x -Z "NV; what 9-0 M M zh ad pav MY MN sh- M o code v vda Compound Compound 119 120 o oo ti uh dy m"? xx with M trom m АХ no 9-0 М M o-4 MM M MM or M Compound 121 Compound 122 o oo o 9.5 koh СО Нн My M. 2 EzS -- МН sa Compound 123 Compound 124 - tt SOS sred Ge! Am MM -4 MOm M le Za MN pod Compound 125 Compound 126 o (o (c) -- du? Ge) shdsh- oo Day nn OD a MOm M m mm M M M.I M Compound 127 Compound 128 fight o or Nn M. 2 ro 9-7 - yin m E Compound 129 Compound 130 De ooo U M rai V n I y M" y Mom M M M M | ru n | r r 0-7 mm lat MM in KM dn 6-47 water Compound 132 Compound 131 bor bo and m"? yo y: m Х І no y | No m Mem m She 4 My M M 0-7 M 0-7 KI Mo - M EzS EzS Compound 133 Compound 134 o o. where) TT. spirit xx rey r zhi M Be | M M | 2 N Im Mom M M M - Ge) and 0-5 he m KO le Compound 135 Compound 136 o o. heh TV ooo /- M 6 5 H | ky, at and Mem Mk 0-7 - M- in KO le 0-5 M Dt Compound 138 Compound 137 o ME. radi 2 tu y: 4 zo sMsm o-0 zm M M- M -- o-4 MTM M 7 dl es -2 ed Kk) Compound 139 compound 140 poluk teh M x r M so o s What 0-0 Mom zhk p pav M - o u ped sia Compound 142 Compound 141 Y 9 Y 9, M oh ah 7 ovuzhn M TK o-4 MM - I EZS EZS Compound 143 Compound 144 o chu Y Chu MM cm dn 4 MM cm M MN MN Compound 145 Compound 146 o 9, o 9 n n M. and Ma M. M o--4 MM o-45 MM M A va vo 8-7 va Mn E E Compound 147 Compound 148 iz Y Z y M y: Same M o-45 MM 0-2 MTU - va Ag le 7 va vod E EZS E Compound 149 Compound 150 bo bo 5 5 y M 5 M s o-i "MM 0-7 "MM M He) Kk va dya Kk ha schu EzS EzS Compound 151 Compound 152 o o, , oh r 75 M.M M Mom Mom M N M. M Oh you Oh where Compound 153 Compound 154 ooo ooo V. Zx 78. ih o-4 MM TM 0-4 MTM m o a i in S dn E EE Compound 155 Compound 156 6) EzS o oo Chuy sv Se mu 5 Sk M. ra NM o MM cm gives 4 - Sun v Compound 157 Compound 158 Her 9 DZ so so sh y M 2 sh 2 M. 2 U / sh- S Lin U / --sh- Sn EzS zo Compound 159 Compound 160 a listen chu y M y xx M | Sha Mi Dn M | M ZD M. 2 - MN d- S /Ln E EE Compound 161 Compound 162 so chu eh M y 8 M 7 (e; mm m act 7 Den prove Compound 163 Compound 164 b oo I B 5 - y M y M vad with EE EE Compound 165 Compound 166 (in) from 7; sa TI Compound 167 Compound 168 ТЯ o oo y 7 5 9 yin a SS X sh NN k N -M - Maura kar, KZ MN Compound 169 Compound 170 o Chuh 9 duh otse vag sova kari MN MN Compound 171 Compound 172 o Chu o chuy shevtse og» MN Mn v Ezo Compound 173 Compound 174 o o o L. Zukh Z y: M y xx y U SS M sho dy; p TU MN EzS and Compound 175 Compound 176 o B | Chui efe deace MM mm y MM m My MN MN Compound 177 Compound 178 ooo 909 h gly ku MOm 4 nok o m ved o m ved Compound 179 Compound 180 (F) Rode; about Chu -5 d ; MM in; MM m M EzS EzS Compound 181 Compound 182 ооо оо0о ДЯ МЯ я sOgO Sha; mm mm mm Ж n M- in M Compound 183 Compound 184 th 9 Y che y Mach y M sOo sOgO ak a pava Me 0-4 mm mem (F) /y chi Compound 185 Compound 186 9 oo Z ke - 73 ih 0 -y M M m o-5 MOM Y a mode ve 2 mn Compound 187 Compound 188 ? chu ooo y: M y vyh m'Z- y de pa aut h Mokh M AN 15 o-i m sshi sy ly vva o vada M. Z / EZS Compound 189 Compound 190 2 9 and 9 de ra - Compound 191 Compound 192 ooo 9 chu and zr 9) | and M | 7 M. | 2 N M. ah Juan 9-5 SHO, M yap I W Compound 193 Compound 194 oo9o boo M/ ML eh m"? eh y m"? oh M | 6-4 n Mrya M sh | d u r 0-y M M m o-4 TMM i Me o fe iy that Compound 195 Compound 196 b 9 o Fe x Nn sh M" M. ho M. 2 OT no M. uva A id ve Y v ayu Compound 198 Compound 197 c) Zuy o oyu M. xx M-M r N M growing x- MN Compound 199 Compound 200 9 chu ooo uva DV uva M, M-mM M. 2 M-mi and about the knife. I and vo, Compound 201 Compound 202 chu o oo wafe chako H 9-07 ZM m 4 9-7 zm Mo m - She S - M. Compound 203 Compound 204 9 Chu (in) oo Ge! xx M | хх ж m-Z He M M Ж n gu M MM tm M х- 5 le o-i m s va I Compound 205 Compound 206 writes about Chu Eh m-Z хх M хх M | - N Y; In M | I N M - o0o-7 "M M M "M 0-7 M M M o da Bodein Ezo Compound 207 Compound 208 9 Chrgo 9 re) Ge) y M t Ge) y M t XM I X nn ki XM I X nn ki u se -- x- MN --7 x- MN Compound 209 Compound 210 2 9 D.chuya -5 a - how long is this? "m M cm M 0-5 Mom w /t x- MN v - MN EzS Compound 211 Compound 212 o o9o 2 o, o Z Z m" 4 ih | In M what is your t i OR zDish MN He Compound 213 Compound 214 oo oo Н H xx M s M v mm y m MM 4 --/7 x- MN --/7 x- MN Compound 215 Compound 216 o 0.9 ooo o s m / x y TI h HM (| D nomzhchn o) Ot o M M " Dt ag Mom her --/7 x- MN Compound 217 Compound 218 (c) chu o oo N YA M M m Mom 4 0-0 zm m 4 --/7 x- МН - Мн Compound 219 Compound 220 Her memory; J. Zso eh M U x- y sogo Z S o- M m MM i4 Me ; ha Ov 9 MN E Compound 221 Compound 222 (9) |c) oo Z 2-3 y: ve and y | But Ho | NOm-ak Mak MN M m MN vd Z E EE and Compound 223 Compound 224 ooo bo t s "Z X | r N M. Ge) M M MAK M M M M in M. MN E Compound 225 Compound 226 obo ooo GU AND M. - N M. 2 XX | - di M МН 5-5 MOosm MOM m - dn - Compound 227 Compound 228 00 zv- o 0.5 / Ge) y M - s ;Z Н M (o) | M M- Hm M m MN ХК Ж mn M pak m MN с х- I Spopuka 229 Compound 230 (e, boo Chrgo ZV. o YOU Mesa M y: | N N | ХК - Mach o-Y mot -- х МН d- МН Compound 231 Compound 232 Ў M o oo usu rt a mch» y m - y ! o- sh- MH in red Compound 233 enantiomer 1 Compound 234 M 6) xx s ek Chu s | r n Cys Mrya n ZUM M Mo Zhe M M M. sh-t MN 7 kA MN EzS enantiomer 2 Compound 236 Compound 235 le ud DZ i SO r N ZK shs sn E Compound 237 Compound 238 osheosche) X | NO k- stre Zh ak MN o MIMO M o to EzS S 240 Compound 239 class (in) M | о щ пе и мя Ж Mсm M EzS o m-n - pod z MM m Compound 242 Compound 241 (9) (9 Ge) boju sr sred EZS (o) M m N k- ono Z m N M- in under; under Compound 243 Compound 244 goyu royu o o Compound 245 Compound 246 battle o in MY MO Me 9-0 ; Mk ma Compound 247 Compound 248 ooo Y Z (5 chx 7 xx Fe M uva X 15 N - M. p M. 2 0-7 MM M 0-4 MM M rove va Jelly m ta pr Compound 249 Compound 250 Ф) еще) о о, l TI r СО сОСо 0-0 М M My r o 9- 0 M M M, WITH . МН and - МН Compound 251 Compound 252 (o) oo 000 - "АХ and poko 0-4 MTM tm o-i M M M o zu o te Compound 253 Compound 254 (c) oy Z 9 chu EE M. 4 Mn 2 M v zha dl no- MOm y d-- MN Compound 255 Compound 256 i) oo o vy lavace H no 0-0 M M M. 2 o o Ж M M M 2 I - MN ey va MN Compound 257 Compound 258 2 9 boo h s ; s МY za y t, B m, " water; d- MN EzS Compound 259 Compound 260 (6) o on plague oi y mu" Ж 8- | no o- Ж n u zh M M M 0-7 ЖЙ Z Y MN that 7 le EzS Ezs Compound 261 Compound 262 on o o, AN o 9, p- N Id! ih KYA xx Max M. s MN M M M 0o-i M M M IF) 4 oon Ka 7 in Za EzS Compound 263 Compound 264 he o o Mn GF) o I 8-X - M o av a WHOSE | nn mmM Nm ee V VYT more 4 KE m t MN o- E o a MN EzS Compound 265 Compound 266 o heard ooo - we ysy N | Ge! y M y Mem MM 4 more EzS o Am ky (F) /y rya ko EZS dy MN Z Compound 267 Compound 268 (c) O, oo0o o rya xx g t ZM Ho | N I o-4 SM TMO m р р МН 7 v 5 le ved vs ro Shk Compound 269 compound 270 o o m o o o Mn Chl, M and we ! shh and muscle ! shh cho in: M cho cho. M 0-4 0-7 er esryah EZS EZS Compound 271 Compound 272 ooo o chu BUK U y -- But M. 2 M. zm vet Te SOz Ezo Compound 273 Compound 274 ooo ooo M re y M" y M M | 2 N t M | s4 A To z, | vod, z, | Du EZS EzS Compound 275 Compound 276 o or Y 9 7 s ; y M M EzS z /t EzS Compound 277 Compound 278 o uh (6) oo y M Z x "M - sec zlo FIN mod Z Mem tm z ЧУ / - sha Ezo Compound 279 Compound 280 o chu o oo EzS xx M x EzS xx m" -sh8-- Compound 281 Compound 282 o to TZ se ego N Z - MN 5/7 - MN EzS EZS Compound 283 Compound 284 and 9th Z Compound 285 Compound 286 "KA Tov v; mat 2 s r? 0-y M. m vas o Compound 287 Compound 288 9 o o o or EZS Z mch EzS and: m"? их I KA BY A kA Tsi Compound 289 Compound 290 ooo Z KU EzS zi sm | r No r Y- m XX nm o- Mnyh i - M nada Z et v EzS SO Compound 291 Compound 292 o to DZ se so Н M no 0-0 M sm i no 0-0 Моm y in шщ- МН i ш - MN Compound 293 Compound 294 o 90, o 0, i r N M. - Myu M. - Ma i M ry: K Kol o MN E on va EE E E Compound 295 Compound 296 oo theo o to all ZM that "XX, 0-4 r 0-4 CM TMM c) to Zhov va MN E on EE Compound 297 Compound 298 o oyu Her Z afe so N r M v? 2-0 SU 0-2 ST Go ts shsh- MN kA MN r Compound 299 Compound 300 9 Chu ooo s ; with M M. - M. and | Id! gla FC t, o o - many M - MN - V! Compound 302 Compound 301 o chu o oo rt Feb; Gee! ru M 7 M M M-- M dy va Dt v MN E E Compound 303 Compound 304 (9 - In X si 8th Hri m m M. um Fata; Fe: Me rum r ruh E and E Compound 305 Compound 306 c) o o oo t -5 OO -5 Fe Kv; c) pF: h-0 M m n: 5 Du zn no: that Dt zn E E Compound 307 Compound 308 (9 OO -Z E Compound 309 its deuterated derivative or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutically acceptable a salt of any of the deuterated derivatives of these compounds. 35. The compound according to claim 1-34, wherein the compound is in the form of a pharmaceutically acceptable salt. 36. A pharmaceutical composition containing at least one compound selected from the compounds according to any of claims 1-35, its pharmaceutically acceptable salt or deuterated derivative of any of the above and optionally one or more of: (a) Compounds (II): n Seya E E M sn (Kk) C) its pharmaceutically acceptable salt or deuterated derivative of any of the above; (5) Compounds (III) or Compounds (PI-4): on (c) (c) M su M y (1) (c) o on or c) IY |c) M M N N y c) c) |c) c) ; (PI-a) its pharmaceutically acceptable salt or deuterated derivative of any of the above; and (c) a pharmaceutically acceptable carrier. 37. The compound of the formula ? (Compound 195) its pharmaceutically acceptable salt or deuterated derivative of any of the above. 38. The compound of the formula R o eh m"? 5 m ДЖ НМ, 0-5 ММ и Й y (Compound 195) or its pharmaceutically acceptable salt. 39. The compound according to claim 37 or 38, wherein the compound is in the form of a pharmaceutically acceptable salt. 40. The compound of claim 39, wherein the pharmaceutically acceptable salt is a calcium salt. 41. The compound of claim 39, wherein the pharmaceutically acceptable salt is a sodium salt. 42. The compound of claim 39, wherein the pharmaceutically acceptable salt is a potassium salt. 43. Pharmaceutical composition, which includes a compound, a salt or a deuterated derivative according to any of claims 37-42 and optionally one of the following: (a) Compound (I): an acceptable salt or deuterated derivative of any of the above; (5) Compound (I) or Compound (PI-4): he (c) (c) M su M ; (PI) (c) o on or c) IY |c) M M N N y c) c) |c) c) ; (PI-a) its pharmaceutically acceptable salt or deuterated derivative of any of the above; and (c) a pharmaceutically acceptable carrier. 44. Pharmaceutical composition, which includes a pharmaceutically acceptable salt according to any one of claims 37-42 and optionally one of the following: (a) Compound (I): n Seya E E M sn (vk) C) its pharmaceutically acceptable salt or a deuterated derivative of any of the above; (5) Compound (I) or Compound (PI-4): on (c) (c) M su M y (I) (c) o on br c) IY r M M N N o c) c) |c ) c) ; (PI-a) its pharmaceutically acceptable salt or deuterated derivative of any of the above; and (c) a pharmaceutically acceptable carrier. 45. The method of obtaining the compound of formula (1): o ka (va Z 1 cha Kk ) t N M Z 7 Kk s Z (P) y ; (I) its pharmaceutically acceptable salt or deuterated derivative of any of the above, which includes: the combination of the MH group of the C ring and the OB group of the B ring of the compound of the formula (U-1): at? НМ о 5 ОН Кк s Z (vi) and z (X-th) its salt or a deuterated derivative of any of the above, where: - ОБ is a halogen; - ring A is a phenyl, a 5-membered heteroaryl ring or a b-h-membered heteroaryl ring; - ring B is a pyridinyl ring; - ring OO is a phenyl ring, a 5-membered heterocyclyl ring, a b-membered heterocyclyl ring, a 5-membered heteroaryl ring or a b-membered heteroaryl ring; - X is 0, MH or M(C1-Cdalkyl); - every CI! independently selected from C1-C2alkyl groups, C1-Chaloxyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl group; - t is equal to 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n equals 0, 1 or 2; - each KZ is a methyl; - each K4 independently selected from halogens, an oxo group, a hydroxyl group, a cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached form a 5-6-membered cycloalkyl or a heterocyclyl ring, which is optionally and independently substituted by one or more groups selected from halogens, C1-C2alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2alkyl groups and C1-C2haloalkyl groups; where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C1Ocycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr -groups where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2haloalkyl groups, C1-Calkyl groups, hydroxyl groups, C1-C2alkyl groups and C1 -C2haloalkyl groups; and - each Kb is independently selected from hydrogen and C1-Chalalkyl groups to form a compound of formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above. 46. The method of obtaining the compound of formula (I) o ka (va Z 1 cha i ) t N M Z 7 Kk s Z (P) y ; (I) its pharmaceutically acceptable salt or deuterated derivative of any of the listed may. - CHOM (above, where the O ring is a; which includes: Z the interaction of a compound of the formula (X), its salt or a deuterated derivative of any of the above with a compound of the formula (2-1), its salt or a deuterated derivative of any - which of the above: I Both M, Hv she M I OM i VI and PA yan pe More I-i I: M hui i IK zd T Y Ku sha r y i ny r SHO z Ka z ro B I mya y shchi a aa ey it В. НГА я "m ; зуше Х рай Х ро Гости Ко и С н- ШХ и щ M, Х щ dО В where: - Oa is a halogen; - ring A is a phenyl, 5-membered heteroaryl ring or b-membered heteroaryl ring; - ring B is a pyridinyl ring; - ring OO is a phenyl ring, 5-membered heterocyclyl ring, b-membered heterocyclyl ring, 5-membered heteroaryl ring or b-membered a heteroaryl ring; - X is 0, MH or M(C1-C4alkyl); - each CI! is independently selected from C1-C2alkyl groups, C1-C2haloxyl groups, C1-C2haloalkyl groups, C1-C2haloalkyl groups, halogens, cyano group and hydroxyl groups; - t is 0, 1, 2, C or 4; - each K2 is independently selected from C1-C2 alkyl groups, C1-C2 alkoxy groups, C1-C2 haloalkyl groups, C1-C2 haloalkyl groups, halogens, cyano group and hydroxyl group; - n is 0, 1 or 2; - each KZ is methyl; - each K4 is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(U)K- B?7-groups, or optionally two K4 together with the atoms to which they are attached, form a 5-6-membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted by one or more groups , selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl groups, C1-C2 alkyl groups and C1-C2 haloalkyl groups; where: - K is equal to 0, 1, 2, 3, 4, 5 or 6; - each U is independently selected from C(К5)(Кб)-groups, -О- and -МВа-groups, where the heteroatom in -(У)К-К7 is not bonded to another heteroatom in -(У)К-К7 , where: - each K5 and Kb is independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups and C3-5cycloalkyl groups, or K5 and KbE on the same carbon atom together form a C3-5cycloalkyl group or oxo; - each of 5 and Kb is optionally independently substituted by one or more groups selected from C1-C2alkyl groups, C1-C2haloalkyl groups, halogens, hydroxyl groups, C1-Chaloxyl groups and C1-C2haloalkyl groups; and - each Ka is independently selected from hydrogen and C1-Chalalkyl groups; and - K7 selected from hydrogen, halogens, cyano group and C3-C1Ocycloalkyl groups, optionally substituted by one or more groups selected from C1-Chalalkyl groups, C1-C2haloalkyl groups and halogens; - 4 equals 1, 2, C or 4; and - 7 is a bivalent linker of the formula (r, where: - r is 1, 2, 3, 4, 5 or 6; - each Y is independently selected from C(K8)(K9)-groups, -O- and -MABr -groups where the heteroatom in 7 is not connected to another heteroatom in 2, where: - each K8 and KU is independently selected from hydrogen, halogens, C1-C2haloalkyl groups, C1-Calkyl groups, hydroxyl groups, C1-C2alkyl groups and C1 -C2halogenalkoxyl groups; and - each KB is independently selected from hydrogen and C1-Alkyl groups. in Fon We in Z YAN SK NINN KO zha Z psych Already sezhjok ShNM tya ikrya fesha Hake sezheu OVO kn p p : Spolyaa i : Compound 5 and Spotzha b va ave | av. E vu : pi ne E tu B ! I By "be; dk, de shk i Zh. sei dk 6 M HUK 2 i Z sire ki Koh i-yi sha shi v NI v on NN s V OV Y Ne AV VINN rova t she I she ROK Voshi VO vo ne ee KT ож ТОЖ жу : Spolena Y : Suma tuUveh I | Spvluyuh Z : EE dk Z a і - od I Z sy dih sce sce o B For. Sha EN. wai ЖЖ V p shi hvo S Not until nn shi vs: NN NN U KE Ya Fig. 1 А В : і і N і ket ek N і-ya KU N KE ee : і sya 3 U GU 1 | SKU Tower of Ii! In shlzhna I N R | and ? And and and and! : i NO 1 N i : Z N their i i i 1 : sko N i i N . is and: see AJ OV det ak o is I s KO ut N i vve iv tu A Me s xx | they sing, A E Y N Z SCHE H her i ii KU 3 1: N y t z N i von YN ND MNN en o NN NN i ri nya otnave m N V that "shchy rr edition i still ey ru: tru, siy N y ev At, N di OO sk «kc yK vit, y N shi pk still ON xx Ky ho eko BE. Cross sh- ach. ko ME N she Ne ros shk as N ! 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UM scho OO KE: SCHO y ky N Ka om ked o SCHE N FROM day to day Be ' From spots: E lodh ya -E i ee i N E -h ih - N IZ i N : ; IS ! i IZ N : N i I N : i N mot i Kt i day : tazh myh Z N i sSzhnUluny i o ESromvyna Z So buroniyuvy V i N : : i N : : i i N Kechynk : i ov : kv ! ME E sho: MOM N r koe MN i ov NK NI Zh z ; НЕ о, и зо зав о ЧНИ a NN ki ES и КОЖ oi opi и -- and piku Zhe i : : Z і VU і o IN luku ze I і: щ і Zhoduetvot і і і Codes і . вх ЗК НН Z и Бе : N I svi o NI ves VN V i NE UM oon MI Ko le i VNOI sche ke y o I ozhno: ME MY : KOobeh : sho Olek h o En shki N EOZE COKO rob 7 : ! : oh them! ! : i N Oh N i N : : i : E i inn nn nn nn nn nn nn nn nn nn mn nn nn nn i sko : sia i : : ! Seny yat: robbery Z: ko Kh: ! 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OT o o min ny ZK DY m sf VE ozhwa t V uh Kino o zh zh i ody EM en N : roya Still Z re zh 6 ve KM: SHE : : ros zh i i Penal y | i: unya i 1 zhpolyna Z i MORE: i I U N ruchok java N i ! Snaluyusyu i t i I i V b I i : j boi V sny VO di OS OVO i : in XE 7 i and Za ze, | There are 5 i she : i 8 i shu o - s es : I vati zkdech zhk! ех соди цк EN: НН 1 en VE niz ne von i; V a ge shi she BUT YN i she chi: o she Oh V N and what sb Zhe and TOLOYet? ШЕ ШШ DATI o y: A ZVO YN E that і ї ШЕ з ke NN ех ШЕ : E і I Нож я KT : : : N Z KI N ko і h N E Y EE Kk kkkkkkkkkkkkkkkkkkky ; and: Evidently and. : - en nn nn nin H : E; : Sazhmerna I | kt that I : E gЖЯ N I | ' : on : dov | ! E about PI s, i ENN | Z i ovo Her hole Z for and VovyT write WA YN NE Z deti vro N : he V IK ze : what entered your M M SHON r i SHY. ve v shi s oo : mTl sonny NOI ookoZ de. Y y V N h azh y y yat i : eh y sh-h Is uk sk IN via r Moy t dnk i Э Х і a de Kovaya scho E ov N ! 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Shi SHE V: a V vna v ii NI Noya x DY NK NNYA o ze ZE NN E si now Oh WITH My Z I -E 23 ik N ! KE in us with ZM DI KOM with zhe she NN, she She in her pocket she M she A long time ago Eat and you Don't TOJ - yan Be o shle, Zhov don't burn de Vin Z zheou osi. OVO shin vti N i : i moe Z x 5 : 1 - 3 5 i KOH E : AK N ZHE N N : | ! N : | ! N Her | ! N 1 N IN N : in z | h pt KVKe : ke che N and kavaluka 1 | Khtnaluna 153 Kak zhka a i 1 Ь N Я : и ХУ Ma Н : | i N : N : N : | ! her N : | ! ож N: in shcha | chn! HO N 1 t h ve N OK : Ken Nya N i Mche nn CHYNNI as AJ Z : ET 1 koe ny YN N Our n s y : Bavd 1 - y y IZ: I am still gay y i KS a eh yku N y o i ZNV» YAN KZ NK Z y ; ee IZ B) Se ko 1 zh vina she BeLNYA x N GU en AK Ne No Z 18 sei, Hom x KE ko i 1 z rech Khivh Z I. N is a child and lady eh OK t shZhet jin Zh M 1 hi v o Same Moi yi yi shi: N yi shou - o NV N Mk I Fo yi : photo, TEM. N nie y Her Her x N So od OSA ! what N and ! N : «OD : | ! N and I: and TO are one single photon. ! і spades t porn Emo ah і і Yenoluka 1455 | Spoluma 153 about Yazraluy TA : | i N i | : N Her | ! N : | ! N : : and | i - N V MOZ N yah F : ECO dk N : pOSPrE | Oh! OOJya Y 1 pits named N ko and Zh syu i OA i N : de tt | maje hu eYa! koh o x K y. cho x g z che, 5. i a. i ki x. sy E shin o CHE pi SHY M: p ni 1 VAS VH Z OO sho POT. ef Ka i VK VN ALL I 1 KU i V U V Ki SOU still y U y ZO KI I yah ee OM N y oy same shen AK ОХОжеж lozh shiv N OV, N rol, х ROL y OKO zhh Ж ОК : | ! N : | ! N : | ! N Her | I N nn nn nn NK KK KK KK KK NN NN NN Fig. eats food 15 ig. 1 (continuation of 15) N shtuchiihmagiyu t V : NN Я и Я и ! SONYA: Yenuma IV: sloluka 4 H: и 3 H: i: H! : : N y dk lam t och N se Ж N KK, h what N N what My OA, t t X So 3 i i OM N his x I N o i E : u ze i od kktsi semu N Ж- k ov: ож pі re u ZV N і if E payu « tk MK B s і 1 a KU U GU N OK What: щ "PI. ve ZU i: t ok ih 3 N i ІХ i 5. OK ME x Medusa N M A eh KI. и E claim 4 Z. i Z i zh s Z IZ 3 : xx tr Wild gardens : Y po uh DIZHyu, ik kyu ih U t B, vu Ka 3 nin Ne meh: ZNU nn BUT YOU V y Kut dyh pen HOW 3 and yoche she N Z du. i Y E pk as Her I ro x r x RO ZHOody Z : 3 : 3 i I It's time a aa aa aa aa aa aa aa aa aa aa aa aa aa aa aa aa a a a a a a a a a a a a a a a a a a a a a a a a a a a p a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a Z ZHE 3 I Stapuka BIV SON uUKU YAZ : Spolena 150 Z N 7 i N i I : i i I i i Z N i 3 N x i oko 3 ! There is still vv I KE N ON ZU PO SCHE e SHE Z N A kru ve xx, Kaae How she squeaked scha oz 3 N ge V GNE Ot those SHO Kon Z N is i: x V RU: this N x Vod 1: SON U shcha 3 N Mo creatures Z rode in NN My o U 1 N SHE V KT Tu Sanni WIN: Z: zatv I s nn: I: S DU Z N E KK OM, Z KE Ko. their x SHE Oi I N xx ny pd sec MOV x dy me se o HOW well. Ж ж Kaya U 3 RO no rya Zhirni, ro EObre y : N Oh o y KO 3 N E: de - m y with N : y I : y 3 and I I Z 5 Я ! nosha mi mi i i p vy Z o py N zami RY same day Her mV pe NO i I slovuka B Kpolentsi53 her field 3 : and I : ! : ! H : and: ; N i N i i - I N OK : B B i pk SCHE shko i Ne s N MN Ne s VE Me Z I NI A Z: NVO Pk Ne SHE ' she UNN zh OVO oi oka NE N SCHO sia ila Zhe z Kos o Ya i Fk man x N p Mav she Za bek i: she Ma rRSHN Ko lo Mosk, and hE shk iy zhd ny ne to a NYA NN SE N Ne UMH myh U: Ot Bo Ky kim 1 ho pilu vh 3 RO peki Rozhe N U pozhTtya V I N Ou: She y y 7 3 year Ah ro oy y ne Z i N y ko I and N y I and N I I and N y Z (7 y I sya . Y Fig. 1 (continuation of 151 nin p p p - y - se DN i pacti vi N bucket le compound 155 OO SdevUe v ! x E : i : ! V i N i N i s V i BE xYA i I 3 : N E r o and nothing N -h kosha Zh i letyazhkhy K. KZ N g as ih t B m I vd sya and their three Kk sha t xx i SUM i Zk SO VN Ash B Eimo VK modati s 5 g V as Mo Mo she ! : ay tk i V sho ХОВ koh KE oon skh shiy kesh meh ni M NI may I VNOI po nie 7 shi i t one AT MO N yi ku i M ! "A How; and be N i N N i V i 1 3 and ! sh- son-in-law souv in KI 3 shto konu ZHI and Speolikhd 157 rolu and skol Uka 3 and N i N i N i N i N i oh: UKOOT Z. i vu N yav Shov sh a. iz ee i ESNEvnn fa i taya SVY Z poke du, and kosh, the dog is silent che k. i I N M sho oh, s t N xx su: 5.1 i Be 4 KE 5 zh Ж what o Ko KUSHSYK KZ oNNe NYA x M ŽY as oyu dia kosh J OM m ze NNYA Z ze vv v i KE s i i nie KOHO kak kn u i ve sh 1 Di: she zha ek kkd Zhe mu sp KM I Be tyu MZHK. Z A : I i Z i i i i i i and N and N and N and N and V will pour yatya o nin von pi po an nn t vutusttiyu o them wash KO, go pat hook N Compound IC Sunznuka ZBE and Compound 105 i and he and N and N and N and V i shk and shu v h i ve ve Y field po so uk Ko Ne Z i E iya ke pro ok fen, vid, ma na v schi; Her. pan НЙ что Ж Я 5 Н я х r что ХН вся и poi S na tlu N with m Ж stoma p How | ше ву и " СХ ВК в и вод ХК, Ср SE о джики ой Me ВКМ ДНЯ шк ТАХ sa: tm a: Я i У К хи N ve te Ш ОВ вена SM. rooe o schuih OH ho N ХK y: ve I What Oh kh y yy N y t 7 V ke i i: shchih N i N i i i still how else "u Fig. 1 (continuation of 171: sznazhav TB and strings KV Y similar which and OO KOOTuv them o Compound M KO Zhunkhlev La ' yi KI Ya maklvny N 3 I Y N 3 K N 3 3 I Z E N y ts K KE НН: ше: у НЗ: и . sito Z ІZ h E B Voloh Z: N : a ot dr ay Z Z ZH BI em k-t E Vk i V YN Zh j i N i pk ho y ha I v i o ZK tia Ua More; Tk. im SYA KE Ший ЦК я 1 ки SHУ N ши ши ше de: ke NI NY SHY U: o NI en NN S OO Shchenya dl e E i u i Kk ve NKZ Kk sh Zhenya: - N OH shli - Z nya h sce OK ОЦХ Y N i ZHE y i Di E EK bo N : tr o i N rya Z E t i : : i I : 3 E : x 3 i N i KI sk Di E N i Ktzusychezvos Z Z u samu Kk ke Z : to Svovluna zakrosa oluva mo io Evoluva ZB i 3 E i N i i t : i E : i V I z N : I i i i i ila Fr Z that Kk I g N E NI zov. Ko i pe zhi OO ShKOl : j di. N : v y KE pyt ee ha i : AN i SHE Z i Z: : i yi V pe : zna zhi i te MAE Mony MVKOO v i o : : U tok tk U I kv nn i No i ne Z NOVI і ke "Kos hu KN Z Bak В B Kk sche; і pe х I I ххщии Bo х х U s k Na N y y y y y r y Y shem m NA NN KoU kh y Ba o N oj y Tok y TE y E in y. syu tyu KO iM Z zhu h IZ sec KOHZ ro N me i VE : : V I : : Z E : nn nn i nn p kn p i i i g N i - z KI s shield, TYA - o x : S s ZHE Z sto i M KE t ssh TI N o Yepoluva MUZ 00 blyuluva tive | Spolu KH : : N Ya yi KE t yi KE N yi - 3 I N : v a V shk Y i E De NE 05 E kozh o ! N ; remember Х ох Я Э: Я и и ге, Но тяж Я Б В Б Я m, ЧЕ охо КУ шчи Ки ша VN: ОБО ОЖ an i в ев ММ I si o KE и I ve хх macho В U s y shk z I what i z cha KU N i po o o AV V 35 nya Zhoko Kk Me. che I Ve Boundaries a nn A VN V o o uv v Bady shk vk o ME o a a: eye she r zh I oj zh ry chere h VM i hi pn ya VO Sho I she she sh y KI I N y 3 E N i 3 K N i KE N i IZ N o . ; , ; Fig. 1 (continuation of 181 and Kama nUa i Z Khvala 1UH : Snolena Yuta : : : N Z t i N Z t i ! H i i : IZ x ih U 5 t i yav E ko a : until Z : Tk Mr spry i vn Hshe ssh nim M Memu y sh: schy svy shy: sshe shy shy ov uyu pi en A BONN Z NN NN: KS NIC t. Voi VZin nie Ma Zv SV NI SHE Z s o za ON NN pov di nia і ! as t. And I sleep ny NI NN s: TsKU t І we sey MY ik ze u OKO she te і i : ETO We : p v Z: eri : ; : І і і 5 і і і E: : і x V y h N IZ t i u hm as I i de Fk i 1 Mt oererkm Z IZ J eulvnm V t spe ta i Ko Kesyuuuva TIK I pk YOU her Yadoluna i i i E: : i i 3 E E i E: : і : И : і і ! | Yakov і і 1 I pu BU і х іх і х І Kos Z po sho kon Kvy і ! but KU I deya v zem GYAYA I Z і i som VE I hop V o ME : vo VO se ik a our NYA SZSH i koi i i 00 skouzho Z shiy ZK v ne ZA pi i i she she: i i kiy i shi a ni I OK VE VV v : BOZHOth U t dok i snie - ke i i 5 ; Z Be : : І І 3 B і і і Е: : : і х В і х В і І і і і і 5 5 і і ! : Kivalena ЗХ і і 5 і і І Z і і і I і і х 5 і х х 5 і h : і V I Za і N Z koe shk tss re i : s: NN: a NI NE ne ery vo would Z tui Ko ; whose x B MK a she 5 m i y She and her KU N also Her tt rukh yakky Uzh yi sir: p. he Ya et in KI On I 53 in hv ky S KON i h. kan and not NNYA i One thing | se v NN ve B Bod EK NKU Z ne sksyunu OBO: y day oh WMO KO seni I and Her s, IZ V BNKU E H. H. IZ t x t : v i ! I и и и и и В и и и и и и и и и и и и и и и и и и и и и и и и и и и и Fig. 1 (continuation of 191 ntnnmnmtnmnlnlzhlzhllllmea shany kimi pp poven : sStmzluva TYA onuka g vrrhnki zh TK : : SKLU ka Htnalukha I KTESKERIKEV EK : : : і I і I у. і . і E shi azh ve ! Her Vo cha sho і і. B BO po KK: и бю Oh ped ih mi kot My r o be 1 how o vod: TOB she she ke o BO OVO Geya i y WE V Z yi su gYA KZ p I o Ne BYA h i i ko Z x v Z I I KU N : she Vo M V i en nin ne o NE Sho Ka she ov I and EN tuo Y her in VO : i: CHINU St Ne z oy eh M NN i tiy "where her i I I shk p. zhit point still Y dyny : : V : | : : і I I N U : і U : nn nn nn a A A A A A A A A A A A A nn A A A IZ i I ts - N i Spoluna food of slyolum 185 | Senoluma 18 : : Um 7 t PO Z y N i | : : і I : ц і pak : і I у что З Ох : і NO still sne і і I ѕок і ші and ме ня кое in ОКО з ШІ Ш. shk SHY MN. Sassn V : yn same Siva na shk o On V IN VSE yi sova NU sh B xx KZ i oo : - х 3 E 2 ku N oyu p ey y y rok zh. 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Ko nn m i: Z vi Ve SHE sne z: Ok I: IN Z Z nn i SHE DE: NSHEZVE, em i NK Z i da oi bank M drinking with NN Z oku t: same sen ov e ZY Sh tn KI nen In ih u CHE i de shi VOM I N shNE vn spek BC : 1 j KI i otu izh I Y t j ro : : KIN KU Z i side N N zhe N : V ey OO: Cauchy : I -e Z v ro I 3 rya y Nya N y : Z m t rai N y : 1 t N : 3 y N : oman NN o V NN a NN Fig. 1 (continuation of 211 o nn nn o Eve and Spa ZK I suka shka Z i ! x B : o x B m N and spring S: IZ U : ped ran I mas yin p: vo v go in and ZD M» MY s ol V ZK: Ku shu li . i scha pk 5. How V : x N Kt I T N «oi Mn Nv ki m y CHO N Y vena SHU KOT - yi KI Eh ka yat t muh dey : y KI yi kre: ACT : y Ne vo o SNY NI same 5 i B yo Y KT oz I U si ha and I N M Every My To vv : y : N y? in N 1 i i : i pn p NN V 0 terkt, i shk uyu VE, : sake ery tr N o slevuka i | kpoluka. I ! U olnynhyu yam i i i I i I N ! i I N N i I N N i sko | i 5 g i V to, Yakov ah i Bo i i Z NN VO ME YASNE ih i vo Z Koa av V NN shin M ve VN : peshe shk shSHK BE bya v y ion a y y Mody du data so K.. en i NI OY y; vy vky. shields o sy zh an i sl: ШY to Ky yashchy zhk Z ras already t ke vve: for Be sh VE V znan pOH N Uh KOopdna h y ka ROB Ot yi N N OT N r, "in ro k h..-.14 N Ko | K, i B i t u N 1 i N i N i I N N nn a p a a PK KK KK V V DO i N - sny : Eh tv hkhamots NK, IZ they NE i I vyv 3 7 I A Ku nyK I ro Svoluka 5 : ne i i N i : i I N N i IZ : rech N : | 5 And 2 pa and i ih I And p. MOZH N di o y N yi E bai i v Be ne i VN Ne EE yi i m A m NN od i M She yi B yi yi zi "py ih KO: J yi dih, Se N : to a V VV Mn m ne M WHAT v ven NI y si yak a ve M ZM En ih och t ozhzhju i hro VN pi ZOVNI di Z ne Z je Zh delkktuy Z ih i es Chizh. shen y ZHVO Oh KK HY - ost Y: and her and N b Kok! 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EE JANV Woreo STAS Fig. 2 (continuation of 1) stands for: vi Fig. 2 (continuation of 2) inherits I pklvtya yah I addkloyuu guide peda Fig. 2 (continuation of ZI The name of the mutation «lk The name of the protein mutation The name of the mutation that is inherited e BE FROM litters h x I in the report even vyy syavy nyny rizzevanenahza Zazadsn pas y t, prp lam svi DOBA: ker sadah to dogs -y equal chenikiV Z A-a ach spos viuVnchAVneKI giv 22175 Z17BipeA MASS riv Byamme ssheado shnuknenaT Ve iAgiivka Givjae names dao No name Squirrel sht ia VO de ZE MA DON ne «nina «leUVozA ge puh UMH sot ZVT - suzvaschich and piny ni Neshze nzvm bipei suda tai, wa Fig. 2 (continuation of 41) Name of vyta kYANK Name of mutation lion Name of vmeutanih, still five or one day 02010001 Fig. 2 (continuation of 5) Name of DNA mutation Name of lka mutation Name of inherited mutation in the family ТУІХОХ Uh biv V met mitik RATNE - zechany t OvlyaA sepivkt vo 5 pat iaA reprimanded And what R 7! "The leader of the city" And the leader: "They have a great success in the world. In T2OA, there is no white space in the IaEor" Fig. 2 (continuation of 61 The name of the DNA mutation is the name of the mutation. The name of the mutation is the name of the mutation. SLU "U ek ssh zhut zh nya pat 54 METO i te "ladu tdv inn Srtnavehu dilnk i y Nemyae name protein zara t-- ad pav d sha TEN rukh fan E : ron Vag slya paziv v aziv. dk zhodtiao r.Bendzostivkh to Fig. 2 (continuation of 7)